FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality (this has long been recognized in other industries).In order for quality to increase, it must be built into the product. To do this requires understanding how formulation and manufacturing process variables influence product quality.Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. A presentation compiled from material freely available on the WEB to introduce the concepts of QbD for beginners.
FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality (this has long been recognized in other industries).In order for quality to increase, it must be built into the product. To do this requires understanding how formulation and manufacturing process variables influence product quality.Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. A presentation compiled from material freely available on the WEB to introduce the concepts of QbD for beginners.
The drug or drug combination may not be official in any pharmacopoeias.
A proper analytical procedure for the drug may not be available in the literature due to patent regulations.
Analytical methods may not be available for the drug in the form of a formulation due to the interference caused by the formulation excipients.
Analytical methods for the quantitation of the drug in biological fluids may not be available.
Analytical methods for a drug in combination with other drugs may not be available.
The existing analytical procedures may require expensive reagents and solvents. It may also involve cumbersome extraction and separation procedures and these may not be reliable.
To recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.
The guideline applies to all dosage forms and routes of administration.
This guidelines does not address all possible solvents, only those identified in drugs at that time, neither address solvents intentionally used as excipients nor solvates.
The maximum acceptable intake per day of residual solvent in pharmaceutical products is defined as “permitted daily exposure” (PDE)
Previously, another terms were used like “Tolerable daily intake” (TDI) & “Acceptable daily intake” (ADI) by different organization & authorities, but now usually this new term “PDE” is used
The drug or drug combination may not be official in any pharmacopoeias.
A proper analytical procedure for the drug may not be available in the literature due to patent regulations.
Analytical methods may not be available for the drug in the form of a formulation due to the interference caused by the formulation excipients.
Analytical methods for the quantitation of the drug in biological fluids may not be available.
Analytical methods for a drug in combination with other drugs may not be available.
The existing analytical procedures may require expensive reagents and solvents. It may also involve cumbersome extraction and separation procedures and these may not be reliable.
To recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.
The guideline applies to all dosage forms and routes of administration.
This guidelines does not address all possible solvents, only those identified in drugs at that time, neither address solvents intentionally used as excipients nor solvates.
The maximum acceptable intake per day of residual solvent in pharmaceutical products is defined as “permitted daily exposure” (PDE)
Previously, another terms were used like “Tolerable daily intake” (TDI) & “Acceptable daily intake” (ADI) by different organization & authorities, but now usually this new term “PDE” is used
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.
Analytical Method Validation is a process that is used to demonstrate the suitability of an analytical method for an intended purpose.Regulations and quality standards that have an impact on analytical laboratories require analytical methods to be validated.
Development and Validation of RP HPLC Method for Estimation of Vortioxetine i...ijtsrd
A rapid and precise reverse phase high performance liquid chromatographic method has been developed for the validated of Vortioxetine in its pure form as well as in tablet dosage form. Chromatography was carried out on ODS C18 4.6 x 250 mm, 5µm column using Acetonitrile And Methonal 70 30 as the mobile phase at a flow rate of 1.0 mL min, the detection was carried out at 274nm. The retention time of the Vortioxetine was 2.922 ±0.02min. The method produce linear responses in the concentration range of 20 µg ml of Vortioxetine. The method precision for the determination of assay was below 2.0 RSD. The method is useful in the quality control of bulk and pharmaceutical formulations. Rathod K. G | Bargaje G. S | Rathod G. R | Deshpande O. V "Development and Validation of RP-HPLC Method for Estimation of Vortioxetine in Bulk and Pharmaceutical Dosage Form" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-3 | Issue-6 , October 2019, URL: https://www.ijtsrd.com/papers/ijtsrd28040.pdf Paper URL: https://www.ijtsrd.com/pharmacy/analytical-chemistry/28040/development-and-validation-of-rp-hplc-method-for-estimation-of-vortioxetine-in-bulk-and-pharmaceutical-dosage-form/rathod-k-g
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.
Understanding of Analytical Method Validation Approach in Pharmaceutical Industry. Analytical method validation Verification is a wide chapter and a huge scope of applicability. In different types of methods, instrument, measurement approach all can effect the validation effort. However the basic fundamental will remains same, the parameters, acceptance criteria, functionality may vary depending upon the type of method, instrument etc.
Bioanalytical Method Development and Validation..
Bioanalytical method validation include all the procedure that demonstrate that a particular method used for quantitative measurement of analyte in given biological matrix are reliable and reproducible for intended use.
Similar to Understanding the Analytical method validation in a Practical Perspective (20)
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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
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
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
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.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
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
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.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
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Understanding the Analytical method validation in a Practical Perspective
1. Professor, Department of Pharmaceutical Analysis,
Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. India.
drbmdishaq@gmail.com
Sat Dec 12,th 2020
http://srcpnandyal.com/
Presented at
2. All the information and views shared in this presentation belongs
solely to me and not necessarily to my employer, organization,
committee or other group or individual. This presentation is
delivered with the whole and sole educational purpose of
students and scholars, not involved any commercial benefits.
Thus the presenter or his employer neither claim for any
copyright nor responsible for any sort of copyright issues arise.
DISCLAIMER
3. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
INTRODUCITON
Analytical method
development, validation
and transfer play
important roles in the
discovery, development
and Manufacture of
pharmaceuticals.
Method development is
the process of proving
that an analytical method
is acceptable for use to
measure the concentr-
ation of an API in a
dosage form, accurately
and consistently will
deliver a reliable
measurement of an active
ingredient in it.
4. Effective method development ensures that laboratory resources are optimized,
while methods meet the objectives required at each stage of drug development.
Method validation, as required by regulatory agencies at certain stages of the
drug approval process, is defined as the “process of demonstrating that
analytical procedures are suitable for their intended use”.
Method transfer is the formal process of assessing the suitability of methods in
another laboratory. Each of these processes contributes to continual
improvement of methods and results in more efficient drug development.
Analytical methods are intended to establish the identity, purity, physical
characteristics and potency of drugs.
Methods are developed to support drug testing against specifications during
manufacturing and quality release operations, as well as during long-term
stability studies.
Methods may also support safety and characterization studies or evaluations of
drug performance.
5. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
Choice of Method
It is important to appreciate the difference between an
‘analytical method’ (combination of steps illustrated by the
‘analytical process’) and an ‘analytical technique’ (chemical
or instrumental procedure by which analytical data is
eventually obtained). In selecting a method we shall need
to consider the following parameters:
• sample type (matrix) and size (lot or a little);
• data required (qualitative/quantitative);
• expected level(s) of analyte(s);
• precision & accuracy expected;
• likely interferences;
• number and frequency of samples for analysis.
6. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
S. No Parameter Description/Value
1 Stationary Phase Zorbax SB-C18 C18 (250X4.6 mmX3µ)
2 Mobile Phase
8 mM ammonium acetate, pH: 5.4:
acetonitrile (66:34)
3 Flow rate 0.4 ml/min
4 Detection Wavelength 272 nm
5 Detector Photo diode array
6 Injection Autosampler -Waters, model 717 plus
8 Injection volume 3 μl
9 Column Temperature Ambient
10 Run time 5 mins
11 Diluent Mobile Phase
Optimized Chromatographic conditions
7. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
Analytical Method Validation
Method validation (MV) is the process used to confirm that
the analytical procedure employed for a specific test is
suitable for its intended use.
Results from method validation can be used to judge the
quality, reliability and consistency of analytical results; it is an
integral part of any good analytical practice.
Definition: MV is the process of “establishing documented
evidence” which provides high degree of assurance that
product (equipment) will meet the requirements for the
intended analytical applications.
Why Validate Analytical Procedures?
Regulatory requirements, good science, and quality control
requirements.
8. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
Types of Analytical procedures
to be Validated:
• Identification tests
• Quantitative tests for
impurities content
• Limit tests for the control of
impurities
• Quantitative tests of the
active moiety in samples of
drug
Method Validation Parameters
9. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
Type of analytical
Procedure Identification
Testing for Impurities ASSAY - dissolution
(measurement only) -
content/potency
Quantitative Limit
Characteristics
Accuracy X X
Precision
Repeatability X X
Interm. Precision X X
Specificity
Detection Limit X X X
Quantitation Limit X X X
Linearity X X
Range X X
Degree of Validation depends upon the type of analytical test/procedure
10. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
Methodology
No exact methodology is available for each parameter.
Only ICH and FDA provides the guidelines but not to the extent of 100%.
Good understanding of each performance characteristics is mot important. This
understanding must be beyond the basic definition of each parameter.
Understanding must be anchored by sufficient years of practical experience and
knowledge. It will permit sound and local decision, even under the most
intense situations.
11. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
SYSTEM SUITABILITY
Definition:
Its an integral part of each method/procedure to ensure that all analytical
operations, electronics and equipments are working properly at the time of
analysis.
Methodology:
Prepare 6 replicates at Target concentration and inject into chromatographic
system or check for absorbance in UV-Vis spectrophotometer.
Evaluation:
Peak area, Rt, Tailing factor, Peak height, Resolution (for two or more no. of
Analytes), No of theoretical plates.
Absorbance and λmax
Calculate Average (Mean), SD and % RSD of all the parameters.
12. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
SYSTEM SUITABILITY
Result:
S. No Peak Area Rt Plate Count Peak Height Tailing
1 7356579 3.835 6891 1142687 1.01
2 7348022 3.832 6839 1165338 1.00
3 7338022 3.832 6839 1165338 1.00
4 7351189 3.833 6755 1152145 1.00
5 7351189 3.833 6755 1152145 1.00
6 7340002 3.836 6616 1137949 0.99
Average 7347500.5 3.8335 6782.50 1152600.333 1.00
STDEV 7155.007 0.002 97.357 11294.660 0.006
%RSD 0.10 0.20 1.44 0.98 0.63
Acceptance Criteria:
Mean Plate count: more than 3000.
Tailing factor: less than 2
% RSD of all the parameters: less than 2%.
13. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
SPECIFICITY
Definition:
Specificity of analytical method is its ability to measure accurately an analyte in
the presence of interference, such as synthetic precursors, excipients, enantiomers
and know (or likely) degradation product that may be expected to be present in
the sample matrix.
Discussion:
Specificity generally refers to a method that produces a response for a single
analyte only.
Selectivity refers to a method which provides responses for a Multiple
chemical entities that may/may not be distinguished from each other.
If each response is distinguished from all other responses, then the method is
said to be selective.
Use of the term selectivity is appropriate for the methods based on
chromatographic techniques like HPLC, UPLC and GC etc.
14. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
SPECIFICITY
Methodology:
Inject/analyze Blank, Placebo (If known) Standard (API) and Sample (Dosage
form) at target concentration for 6 replicates.
Evaluation:
Identification tests: Response for compound of interest (Analyte) only.
Assay: Peak Purity of analyte peak
Impurities: Resolution between within the impurity(s) and/or degradants and
from analyte.
15. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
Acceptance Criteria:
Identification tests: Positive response for
compound of interest only.
Assay: No interfering peaks should be found at
the RT of analyte peak.
Impurities: Should pass peak purity of main
analyte and impurity peaks.
No interfering peaks should be found at the
RT of analyte peak.
Dissolution: interfering peaks should be found
at the RT of analyte peak.
In case of UV method, %difference between λmax
of API and sample should not be more than 2%
Placebo
API
Tablet
SPECIFICITY
16. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
LINEARITY
Definition:
Linearity of an analytical procedure is its ability (within a given range) to obtain
test results that are directly proportional to the concentration of analyte in the
sample.
Range: The Interval between the upper and lower level that have been
demonstrated to be determined with precision, accuracy and linearity using this
method .
Methodology:
Prepare a series of solutions (5 to 8 non zero standard solutions) at 25 to 200%
of target concentration.
Inject into Chromatographic system or check the absorbance in UV-Vis
Spectrophotometer.
17. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
S. No Linearity Level Concentration (μg/mL) Peak Area
1 25 % 35.00 1841901
2 50 % 70.00 3697872
3 75 % 105.00 5547026
4 100 % 140.00 7394914
5 125 % 175.00 9352643
6 150 % 210.00 11084071
7 175 % 245.00 12988710
8 200 % 280.00 14846511
Acceptance Criteria:
All the response points must be
on line. (Direct proportional)
R2 (correlation co-efficient)
must be more than 0.999.
18. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
PRECISION
Definition:
Closeness of agreement (degree of scatter) between a series of measurements
obtained from multiple sampling of the same homogenous sample under the
prescribed conditions.
Precision may be considered at three levels.
System precision (System suitability)
Method Repeatability
Intermediate precision
Reproducibility
19. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
Repeatability: Precision under same operating conditions (with in a laboratory
over a short period of time by the same analyst with same equipment)
Injection repeatability – System precision.
Method Repeatability – Method Precision.
Intermediate Precision: Precision under different laboratory conditions (with in
laboratory variation, as on different days or with different analysts or equipment
within the same laboratory).
Reproducibility: Precision between laboratories/Intermediate Precision can be
considered during the standardization of a procedure before it is submitted to the
Pharmacopoeia.
20. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
Methodology:
Six Replicates of target concentration were
prepared using the dosage form and
injected - HPLC or determined the
absorbance – UV-VIs.
Six Replicates of target concentration were
prepared through the complete analytical
procedure from sample preparation to
final result for method precision.
Six replicates of target concentration were
prepared using dosage form by two
different analysts, analysed on two
different columns or instruments and on
different days for Ruggedness.
S. No
Analyte
Peak Area % Assay
1 7432699 101.03
2 7357606 100.01
3 7398974 100.57
4 7349367 99.90
5 7390881 100.46
6 7412006 100.75
Average 7390255.50 100.45
STDEV 31902.34 0.43
% RSD 0.43 0.43
Acceptance Criteria:
% RSD of Response and %
Assay should be less than
2%.
21. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
ACCURACY
Definition:
Closeness of agreement between the standard / reference value and the value
found experimentally.
Methodology:
Assay/Dissolution: Know amount of drug sample spiked with synthetic mixture of
drug product components (excipients) – Minimum at three levels
80%. 100% and 120% of test concentration
Or
50%, 100% and 150%
Evaluation:
% Recovery from the amount added and found was determined.
% Mean recovery of three levels was determined.
22. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
Recovery Studies (Accuracy):
Amount Added:
Amount Found:
% Recovery:
23. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
Accuracy Level Wt. of Sample Peak Area Amount Added Amount Found % Recovery Mean % Recovery
50%
10.506 3631749 69.69 69.11 99.17
100.00
10.506 3711606 69.69 70.63 100.35
10.506 3673683 69.69 69.91 100.32
10.506 3730428 69.69 70.99 100.87
10.506 3713458 69.69 70.66 100.40
10.506 3702716 69.69 70.46 100.11
100%
21.011 7253479 139.38 138.03 99.03
99.74
21.011 7351061 139.38 139.89 100.37
21.011 7311150 139.38 139.13 99.82
150%
31.517 11039927 209.06 210.08 100.49
100.00
31.517 11088563 209.06 211.01 100.93
31.517 11105958 209.06 211.34 100.09
31.517 11205024 209.06 213.22 100.99
31.517 11003028 209.06 209.38 100.15
31.517 11104679 209.06 211.31 100.08
Acceptance Criteria:
Mean % Recovery at 50%, 100% and 150% should be in between 98-100%
24. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
LOD & LOQ
Definition:
LOD: Lowest amount of analyte in a sample which can be detected but not
necessarily be quantitated.
LOQ: Lowest amount of analyte in a sample which can be quantitatively
determined.
25. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
Methodology:
Calculate LOD and LOQ using Slope from Linearity and SD from Precision.
Prepare the solutions as per the concentration obtained
Inject into chromatographic system or check the absorbance.
Evaluation:
Response at LOD and LOQ.
Result:
Acceptance Criteria:
Same as Linearity and Precision.
Parameter Result LOD LOQ
Slope 53080
STDEV 31902.34 1.80μg/mL 6.01μg/mL
26. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
ROBUSTNESS
Definition:
Ability to remain unaffected by small but deliberate changes in method
parameters and provides indication of its reliability during its normal usage.
Typical variations include:
Flow rate: ±10%
Wavelength: ±2nm
Organic component of Mobile phase: ±2%
Temperature: ±5°C
pH of the mobile phase: ±0.2 Units.
Procedure:
Prepare the three replicate sample at target concentration and determine the
response (peak area or absorbance) under changed method parameters.
27. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
Evaluation:
System suitability parameters and % Assay
Result:
Robustness
Parameter
Condition
Analyte
System suitability parameters
Peak Area % Assay
RT
Theoretical
Plates
Tailing
Flow
0.3 ml/min 0.995 3630 1.01 3988943 100.07
0.5 ml/min 0.816 3623 1.02 3986771 100.01
0.7 ml/min 0.779 3689 1.02 3987160 100.02
Temp
25 °C 0.817 3768 1.01 3978156 99.79
30 °C 0.816 3564 1.02 3986771 100.01
35 °C 0.810 3573 1.02 3987612 100.03
Wave length
256 nm 0.817 3267 1.02 3957612 99.28
258 nm 0.816 3674 1.01 3986771 100.01
260 nm 0.814 3890 1.01 3987612 100.03
Acceptance Criteria:
System suitability parameters must pass with % Assay in between 98-100%
28. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
FORCED DEGRADATION STUDIES
Definition:
Forced degradation or stress testing is undertaken to demonstrate specificity
when developing stability indicating methods.
A stability indicating method is one that accurately quantitates the active
ingredient without interference from degradation products, process impurities,
excipients, or other potential impurities.
Why to perform?
Address the stability of the compound
Establish the degradation pathway
Identify the degradation products.
Validate the stability indicating nature of the analytical procedure used.
Forced degradation studies should mimic the conditions to which the drug
substance/ drug product is actually exposed during its shelf life.
29. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
Procedure
Perform analysis for each stressed sample as per methodology using the initial
stress conditions viz.,
Acid: 1M HCl
Base: 1M NaOH
Peroxide: 10% H2O2
Thermal: 105°C for 72 H
Photolytic: 12000 Lux for 72 H
Humidity: 92% RH at 25°C for 72 H
30. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
Evaluation:
% Difference of assay for control (Unstressed, Normal) and each stressed
samples.
Peak Purity of analyte peak for control and stressed sample.
Points to be remembered
If the degradation condition degrades the drug substance/drug product to too greater
extent or do not degrade at all, then alternative action should be taken (eg: change the
strength of the degradation medium or exposure time or heat applied or period of
exposure etc).
5-10 % of API must degrade.
Some compounds may not necessarily degrade under a given stress condition. No
further stressing is advised in these cases.
Over stressing may lead to the formation of secondary degradants, causes disturbance
to the selectivity of the method, requires further development.
32. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
S. No Condition Peak Area % Assay % Degradation
1 Acid 6549579 89.02 10.98
2 Base 6689022 90.92 9.08
3 H2O2 6789022 92.28 7.72
4 UV 6614583 89.91 10.09
5 Heat 6616189 89.93 10.07
Acceptance Criteria:
At least 5-10% of drug substance should degrade.
Stability indicating power of the method demonstrates the ability of a method to
separate the analyte of interest from its degradation or impurities formed if any,
caused by quality of chemicals used in the manufacturing process, packaging,
storage, shipment and/or any unexpected exposure during shelf life of the drug
substance or drug product.
Result
33. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
References
1. FDA Guidance for Industry – Analytical Procedures and Method Validation,
Chemistry, Manufacturing, and Controls Documentation, Center for Drug
Evaluation and Re- search (CDER) and Center for Biologics Evaluation and Research
(CBER), August 2000.
2. International Conference on Harmonization Quality Guidelines Q2(R1), Validation
of Analytical Procedures, Text and Methodology, Parent guideline dated 27 Oct
1994, Complementary guideline on methodology dated 6 Nov 1996, incorporated
November 2005
3. USP 31 (2009): General Tests, Chapter 621 – Chromatography System Suitability,
United States Pharmacopeial Convention (USP), Rockville, MD.
4. Chan, C. C. et. al. (ed.), (2004), Analytical Method Validation and Instrument
Performance Verification, Hoboken, NJ: John Wiley & Sons (Wiley Interscience).
34. Santhiram College of Pharmacy, Nandyal, Kurnool Dist. AP. 518501.
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