The IFCC Working Group on Standardization of HbA1c has achieved the following in their efforts to standardize HbA1c measurement globally:
1. Established a reference measurement procedure using purified calibrators and HPLC or capillary electrophoresis.
2. Developed a network of reference laboratories worldwide to implement the reference system.
3. Begun work on traceability to the IFCC reference system, though full implementation is on hold pending further studies relating HbA1c to average blood glucose levels.
The position of the IFCC Working Group is that the name HbA1c should continue to be used in clinical practice, measurement units should be reported as mmol/mol
Bioequivalence Study of the Two Products of Efavirenz by Validated Analytical...BRNSS Publication Hub
The aim of this study was to find whether the bioavailability of a 600 mg efavirenz capsule (E.F.600 capsule, test) produced by Macneil and Argus Pharmaceutical Ltd. was equivalent to the tablet EFAVIR produced by the Cipla Ltd. (reference preparation). The pharmacokinetic parameters assessed in this study were area under the plasma –concentration time curve 0–96 h (AUCt), area under the plasma concentration time curve from time 0 to ∞ (AUCinf), the peak plasma concentration of drug (Cmax), time needed to achieve the peak plasma concentration (tmax), and the elimination half-life (t½). This was a randomized, single-blind, two-period, crossover study which included 20 healthy adult male and female subjects under fasting conditions. In each of the two study periods (separated by a washout of 1 week), single dose of test or reference drug was administered. Blood samples were taken up to 96 h past dose, the plasma was separated, and the concentrations of efavirenz were determined by high-performance liquid chromatography -UV method. Bioavailability and bioequivalence studies play a key role during the phase of drug development for both innovator drugs and generic drugs and thus have gained a great attention over the past few decades. Bioequivalence study is used to introduce generic drugs of innovator drugs at a lower cost. Hence, a thorough understanding of these bioavailability/bioequivalence studies is required.
Stability Indicating HPLC Method Development A Reviewijtsrd
High performance liquid chromatography HPLC is an essential analytical tool for evaluating drug stability. HPLC methods must be able to isolate, detect, and quantify drug related degradation products that may form during storage or production, and identify drug related impurities that may form during synthesis. .. This article describes strategies and challenges for designing HPLC methods to demonstrate drug stability. It will deepen our understanding of drugs and medicinal chemistry and demonstrate advances in stability that reflect an analytical approach. Several important chromatographic parameters were investigated to improve the detection of potentially related degradants. It is necessary to find suitable solvent and mobile phase samples that provide sufficient stability and compatibility with each component and potential impurities and degradants. This method should be carefully considered as it has the ability to distinguish between primary and secondary decomposers. The study of forced destruction of chemicals and new drugs is essential for the development and characterization of these immobilization methods. Practical guidance is provided at each stage of drug development to develop a forced disposal protocol and avoid common issues that might impede data interpretation. Suraj Nagwanshi | Smita Aher | Rishikesh Bachhav "Stability Indicating HPLC Method Development - A Review" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-5 | Issue-5 , August 2021, URL: https://www.ijtsrd.com/papers/ijtsrd46310.pdf Paper URL: https://www.ijtsrd.com/pharmacy/other/46310/stability-indicating-hplc-method-development--a-review/suraj-nagwanshi
DEVELOPMENT AND VALIDATION OF STABILITY INDICATING RP-HPLC METHOD FOR ESTIMAT...Earthjournal Publisher
DEVELOPMENT AND VALIDATION OF STABILITY INDICATING RP-HPLC METHOD FOR ESTIMATION OF TERCONAZOLE
Gandhi Santosh V , Phalke Truprti R, Chaudhari Atul P
IRO INTERNATIONAL JOURNAL OF MEDICAL AND APPLIED SCIENCES 2018, 1(1):14-19.
PDF
Stability indicating analytical method development and validation for estimat...SriramNagarajan18
Stability indicating analytical method development and validation for estimation of Ceftazidime and Avibactam in bulk and pharmaceutical dosage form using RP-HPLC
The document discusses stability studies of pharmaceuticals. It begins with an introduction defining stability studies and their purpose to ensure drug efficacy, safety and quality over the shelf life. It then outlines the key stages of stability studies including stress testing, international stability guidelines, and development of stability indicating assay methods (SIAMs). SIAMs are validated quantitative methods that can detect changes in drugs and products over time. The document concludes with two case studies demonstrating the development and validation of SIAMs for pharmaceutical combinations using HPLC and HPTLC methods.
Comparative analysis of biopharmaceutic classification system (BCS) based bio...Madiha Mushtaque
Biopharmaceutic classification system (BCS) is a substantial part of drug designing and generic product development and has been accepted as a technique to renounce in-vivo pharmacokinetic evaluation (biowaiver). It appeared to be worthwhile and time-saving by means of in-vitro studies in the presence of biorelevant physiological mediums that mimic not only the predictable solubility but also permeability of the multisource product. Such methodology is now applied as a regulatory stamp to support new and generic product approvals based on other than in-vivo equivalence testing. This article outlines the foundation of BCS, its implementation in granting biowaiver, adequacy of in-vitro bioequivalence studies, principles and requirements of BCS biowaiver by four regulatory agencies such as; Food and Drug Authority (FDA), World Health Organization (WHO), European medicine agency (EMA) and International Conference on Harmonization (ICH), potential effect of excipients on solubility and permeability of drug molecules and supplementary data provided by FDA regarding biowaiver approvals. Furthermore, supportive data provided by the International Pharmaceutical Federation (FIP) has also been given for biowaiver sanction of certain drug products. It has been concluded, that although biowaiver is a profitable methodology for generic and new drug product approval, the variance in the standards of governing bodies demands more critical assessment to establish some unified principles to be followed globally.
This document provides guidance on bracketing and matrixing study designs for stability testing of new drug substances and products. Bracketing involves testing only samples on the extremes of certain design factors, like strength or container size, at all time points. Matrixing involves testing a subset of all possible samples at each time point. The guideline outlines when and how bracketing and matrixing can be applied, including design examples. Any reduced design must be justified and have the ability to adequately predict shelf life or retest period. All factor combinations should be tested at initial, final, and 12-month time points.
The document discusses planning and reporting of stability studies for pharmaceutical products. It provides definitions of key terms from ICH guidelines related to stability testing of active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs). Specifically, it defines terms like re-test date, shelf life, formal stability studies, stress testing, primary and commitment batches, and more. It also discusses requirements for stability protocols and reports, including details of batches tested, storage conditions, analytical methods used, and results. Forced degradation studies aim to identify potential degradation pathways and validate stability-indicating methods.
Bioequivalence Study of the Two Products of Efavirenz by Validated Analytical...BRNSS Publication Hub
The aim of this study was to find whether the bioavailability of a 600 mg efavirenz capsule (E.F.600 capsule, test) produced by Macneil and Argus Pharmaceutical Ltd. was equivalent to the tablet EFAVIR produced by the Cipla Ltd. (reference preparation). The pharmacokinetic parameters assessed in this study were area under the plasma –concentration time curve 0–96 h (AUCt), area under the plasma concentration time curve from time 0 to ∞ (AUCinf), the peak plasma concentration of drug (Cmax), time needed to achieve the peak plasma concentration (tmax), and the elimination half-life (t½). This was a randomized, single-blind, two-period, crossover study which included 20 healthy adult male and female subjects under fasting conditions. In each of the two study periods (separated by a washout of 1 week), single dose of test or reference drug was administered. Blood samples were taken up to 96 h past dose, the plasma was separated, and the concentrations of efavirenz were determined by high-performance liquid chromatography -UV method. Bioavailability and bioequivalence studies play a key role during the phase of drug development for both innovator drugs and generic drugs and thus have gained a great attention over the past few decades. Bioequivalence study is used to introduce generic drugs of innovator drugs at a lower cost. Hence, a thorough understanding of these bioavailability/bioequivalence studies is required.
Stability Indicating HPLC Method Development A Reviewijtsrd
High performance liquid chromatography HPLC is an essential analytical tool for evaluating drug stability. HPLC methods must be able to isolate, detect, and quantify drug related degradation products that may form during storage or production, and identify drug related impurities that may form during synthesis. .. This article describes strategies and challenges for designing HPLC methods to demonstrate drug stability. It will deepen our understanding of drugs and medicinal chemistry and demonstrate advances in stability that reflect an analytical approach. Several important chromatographic parameters were investigated to improve the detection of potentially related degradants. It is necessary to find suitable solvent and mobile phase samples that provide sufficient stability and compatibility with each component and potential impurities and degradants. This method should be carefully considered as it has the ability to distinguish between primary and secondary decomposers. The study of forced destruction of chemicals and new drugs is essential for the development and characterization of these immobilization methods. Practical guidance is provided at each stage of drug development to develop a forced disposal protocol and avoid common issues that might impede data interpretation. Suraj Nagwanshi | Smita Aher | Rishikesh Bachhav "Stability Indicating HPLC Method Development - A Review" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-5 | Issue-5 , August 2021, URL: https://www.ijtsrd.com/papers/ijtsrd46310.pdf Paper URL: https://www.ijtsrd.com/pharmacy/other/46310/stability-indicating-hplc-method-development--a-review/suraj-nagwanshi
DEVELOPMENT AND VALIDATION OF STABILITY INDICATING RP-HPLC METHOD FOR ESTIMAT...Earthjournal Publisher
DEVELOPMENT AND VALIDATION OF STABILITY INDICATING RP-HPLC METHOD FOR ESTIMATION OF TERCONAZOLE
Gandhi Santosh V , Phalke Truprti R, Chaudhari Atul P
IRO INTERNATIONAL JOURNAL OF MEDICAL AND APPLIED SCIENCES 2018, 1(1):14-19.
PDF
Stability indicating analytical method development and validation for estimat...SriramNagarajan18
Stability indicating analytical method development and validation for estimation of Ceftazidime and Avibactam in bulk and pharmaceutical dosage form using RP-HPLC
The document discusses stability studies of pharmaceuticals. It begins with an introduction defining stability studies and their purpose to ensure drug efficacy, safety and quality over the shelf life. It then outlines the key stages of stability studies including stress testing, international stability guidelines, and development of stability indicating assay methods (SIAMs). SIAMs are validated quantitative methods that can detect changes in drugs and products over time. The document concludes with two case studies demonstrating the development and validation of SIAMs for pharmaceutical combinations using HPLC and HPTLC methods.
Comparative analysis of biopharmaceutic classification system (BCS) based bio...Madiha Mushtaque
Biopharmaceutic classification system (BCS) is a substantial part of drug designing and generic product development and has been accepted as a technique to renounce in-vivo pharmacokinetic evaluation (biowaiver). It appeared to be worthwhile and time-saving by means of in-vitro studies in the presence of biorelevant physiological mediums that mimic not only the predictable solubility but also permeability of the multisource product. Such methodology is now applied as a regulatory stamp to support new and generic product approvals based on other than in-vivo equivalence testing. This article outlines the foundation of BCS, its implementation in granting biowaiver, adequacy of in-vitro bioequivalence studies, principles and requirements of BCS biowaiver by four regulatory agencies such as; Food and Drug Authority (FDA), World Health Organization (WHO), European medicine agency (EMA) and International Conference on Harmonization (ICH), potential effect of excipients on solubility and permeability of drug molecules and supplementary data provided by FDA regarding biowaiver approvals. Furthermore, supportive data provided by the International Pharmaceutical Federation (FIP) has also been given for biowaiver sanction of certain drug products. It has been concluded, that although biowaiver is a profitable methodology for generic and new drug product approval, the variance in the standards of governing bodies demands more critical assessment to establish some unified principles to be followed globally.
This document provides guidance on bracketing and matrixing study designs for stability testing of new drug substances and products. Bracketing involves testing only samples on the extremes of certain design factors, like strength or container size, at all time points. Matrixing involves testing a subset of all possible samples at each time point. The guideline outlines when and how bracketing and matrixing can be applied, including design examples. Any reduced design must be justified and have the ability to adequately predict shelf life or retest period. All factor combinations should be tested at initial, final, and 12-month time points.
The document discusses planning and reporting of stability studies for pharmaceutical products. It provides definitions of key terms from ICH guidelines related to stability testing of active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs). Specifically, it defines terms like re-test date, shelf life, formal stability studies, stress testing, primary and commitment batches, and more. It also discusses requirements for stability protocols and reports, including details of batches tested, storage conditions, analytical methods used, and results. Forced degradation studies aim to identify potential degradation pathways and validate stability-indicating methods.
Comparison of stability testing requirements of ich with otherJun Brown
Stability plays an important role in the drug development process. Present work aims to compare the stability
testing (ST) requirements of International Conference on Harmonization (ICH) with other international regulatory
agencies like World Health Organization (WHO), Association of South East Asian Nations (ASEAN) and
European Agency for Evaluation of Medicinal and Health Products (EMEA). ICH guidelines describe stability
testing requirements for new drug substance and drug product. WHO guidelines describe stability testing
requirements for both new and existing Active pharmaceutical ingredients (APIs) and addresses information
to be submitted in original and subsequent applications for marketing authorization of their related Finished
pharmaceutical products (FPP) for human use. ST requirements for WHO are similar, except for the parameters
like selection of batches and storage conditions. WHO guidelines have an additional requirement for long term
storage condition (general case) and accelerated storage conditions (substance/product intended to be stored
in refrigerator). ASEAN guideline mainly focuses on the requirements for stability testing of drug products along
with new chemical entities (NCE’s). The differences were observed in stress testing, selection of batches and
real time storage conditions. EMEA guidelines discussed here are an extension of the note for guidance on
stability testing requirements for new active substance and related products. It sets out the stability testing
requirements for existing active substance and related finished product. The minimum time period to be covered
by data at the time of submission during long term storage conditions differs from ICH guidelines.
The document discusses International Council for Harmonisation (ICH) guidelines related to stability testing of drug substances and products. It provides an overview of the historical background and development of ICH. It summarizes several ICH guidelines including Q1A on stability testing, Q1B on photostability testing, Q1C on stability testing for new dosage forms, and Q1D on bracketing and matrixing designs for stability testing. It also discusses stability storage conditions, principles of ICH guidelines for stability testing, and the objectives of guidelines like Q1E on evaluation of stability data.
The ICH Q1A guideline provides recommendations for conducting stability studies on drug substances and drug products to establish retest and shelf-life periods. Key points include:
- Stability studies should be conducted on 3 primary batches under long-term, intermediate, and accelerated storage conditions specified in the guideline.
- Testing frequency is typically every 3 months for the first year of long-term studies and specifications cover physical, chemical, biological, and microbiological attributes.
- The purpose is to evaluate how quality varies over time under influence of factors like temperature and humidity and provide evidence to support recommended storage conditions.
1) There are four levels of in vitro-in vivo correlations (IVIVC) ranging from Level A to Level D. Level A correlation involves point-to-point correlation of dissolution and absorption profiles and is most useful for regulatory purposes. Level B uses statistical moments, while Level C correlates single dissolution timepoints to pharmacokinetic parameters.
2) The document discusses a case study developing a Level A IVIVC for a prolonged-release hydrocodone formulation. Dissolution and pharmacokinetic profiles from clinical studies were used to establish a direct correlation between % dissolved and % absorbed using linear and nonlinear time scaling.
3) The Level A IVIVC showed good predictability of less than 10%
This document discusses guidelines for stability testing of pharmaceuticals according to the International Conference on Harmonization (ICH). It describes the ICH guidelines for stability testing, including stability protocols, reports, and studies. The key points covered include stability testing procedures, factors affecting drug stability, types of stability studies, and organizations that regulate stability guidelines such as the ICH.
The document discusses guidelines for conducting stability studies on drug substances and drug products according to ICH guidelines. It provides details on the objectives and scope of stability testing, factors to consider like storage conditions and container closure systems, types of studies to perform, and statistical approaches to analyze the data. The goal is to establish retest periods for drug substances and shelf lives for drug products based on stability data from multiple batches in order to submit this information for product registration applications.
This document summarizes guidelines for stability testing according to ICH guidelines. The key points are:
1) ICH guidelines are most commonly accepted and provide information on stability testing in the EU, Japan, and US. Stability testing aims to provide evidence of how quality varies over time under different conditions.
2) The objectives of ICH are more economical use of resources, eliminating delays in global development and availability of medicines, and maintaining safeguards for quality, safety, and efficacy.
3) Stability topics covered by ICH include testing, validation, impurities, specifications, and manufacturing. This summary focuses on stability testing guidelines for new drug substances and products.
This document provides an overview of the ICH Q1A(R2) guideline for stability testing of new drug substances and products. The guideline defines the stability data package required for drug registration in major regions. It addresses testing timelines and conditions for long term, intermediate, and accelerated studies on at least three batches of drug substance and product. The goal is to establish a re-test period or shelf life and recommended storage conditions. Specifications must cover attributes susceptible to change that could impact quality, safety or efficacy. The guideline provides detailed recommendations for testing frequency, storage conditions, and evaluation of results.
The document discusses ICH stability testing guidelines for drug substances and products, outlining the types of studies required including long term, intermediate, and accelerated studies under various storage conditions. Key aspects that are evaluated include physical, chemical, and microbial changes that may occur over time and factors that influence stability such as temperature, humidity, and light exposure. The purpose of stability testing is to establish a product's shelf life and ensure it remains safe and effective when stored as recommended.
Stability testing of biotechnological/ biological products (Q5C )UshaKhanal3
The document provides guidance on stability testing and data requirements for biotechnological/biological products. It recommends conducting long-term stability studies on at least three batches of the drug substance and drug product under various storage conditions to generate data to establish shelf life. It also discusses the use of representative batches, intermediate stability testing, and specifications for labeling storage conditions.
The document discusses guidelines for stability testing from the International Conference on Harmonisation (ICH). It provides an overview of several ICH guidelines related to stability testing of drug substances and products, including guidelines on photostability testing, new dosage forms, bracketing and matrixing designs, and evaluation of stability data. It also summarizes key aspects of conducting stability studies such as selecting representative batches, appropriate container closure systems, testing frequency and storage conditions, and evaluation of results. Stress testing is discussed as a way to validate analytical methods and identify potential degradants.
This document provides an index of quality, safety, efficacy, and multidisciplinary guidelines created by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The index includes over 50 finalized guidelines organized by topic area and date. It also lists guidelines that have been released for further consultation and development.
The document outlines the key stages and requirements for drug development and approval by the FDA. It discusses the necessary chemical, manufacturing and controls (CMC) information that must be submitted at each stage, including details on the drug substance, manufacturing process, specifications, stability testing and other information for both the drug substance and drug product.
The document summarizes the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) quality guidelines. The ICH brings together regulatory authorities and the pharmaceutical industry to discuss drug registration. The quality guidelines cover topics such as stability testing, validation of analytical procedures, impurities, pharmacopoeias, quality of biotechnological products, specifications, good manufacturing practices, pharmaceutical development, quality risk management, and the pharmaceutical quality system.
Drug stability refers to a drug substance or product remaining within established specifications over time. The stability of a product is expressed as its shelf life or expiry period. Stability testing involves multiple stages from early stress testing to ongoing long-term testing as required by regulatory bodies. Stability is affected by various factors related to the drug, formulation, and environment. Reduced stability study designs like bracketing and matrixing allow testing of representative samples and are acceptable with proper scientific justification.
This document summarizes guidelines from the International Conference on Harmonisation (ICH) regarding stability testing of new drug substances and products. It discusses ICH guidelines Q1A(R2) through Q1F, which provide recommendations on conducting stability studies under various storage conditions to determine appropriate re-test periods and shelf lives. The guidelines specify the types of studies, including stress testing, selection of batches, container closure systems, specifications, testing frequency, and evaluation criteria. The document outlines recommended storage conditions and minimum time periods for long-term, intermediate, and accelerated stability studies to support product registrations.
This document discusses ICH guidelines for stability testing and protocols. It provides an overview of ICH partners and guidelines related to quality, safety, and efficacy. It then focuses on ICH guideline Q1, which provides guidance on stability testing of new active pharmaceutical ingredients and finished pharmaceutical products. Key aspects covered in Q1 include stress testing, selection of batches, storage conditions, container closure systems, and photo stability testing. The document also discusses bracketing and matrixing designs, stability protocols and reports, and requirements for stability results and re-test periods.
Q1E Evaluation of Stability Data by Rahim Khoja presented on December 22, 2014Rahim Khoja
This document provides guidelines for using stability data to propose a retest period or shelf life in product registration. It describes how extrapolation of data beyond the available long-term data can be considered. The guidelines recommend a systematic approach to presenting and evaluating stability data from physical, chemical, biological and microbiological tests. Extrapolation may be proposed if no significant changes are observed under accelerated conditions and it is assumed the same change pattern will continue. A retest period granted via extrapolation should be verified with additional long-term data. The guidelines also provide decision trees and examples of statistical analyses to determine if data from different batches can be pooled for evaluating a single proposed period.
Aims: Dried Blood Spot (DBS) sampling is a frequently used method to obtain Haemoglobin A1C (HbA1c) in clinical studies of freeliving populations. Under controlled conditions, DBS sampling is a valid and robust alternative to traditional Whole Blood (WB) sampling. The objective of this analysis was to investigate the impact of storage conditions on the validity of HbA1c assessed from DBS collected in free-living and to develop a method to correct for this type of error.
The document describes COMPACT, a database for analyzing common eligibility features in clinical trials. It extracts metadata, categorical features, and numeric features from trial summaries on ClinicalTrials.gov using natural language processing. Analysis of Type 2 diabetes trials in COMPACT found common categorical features like diabetes and metformin use. Numeric features like HbA1c levels and BMI were frequently used, often with value ranges of 7.0-10.0% and 25.0-40.0 respectively. The database and a visualization tool called VITTA are resources for understanding trial population design and improving generalizability. Future work includes enhancing feature analysis and comparing trial populations to patient populations.
Comparison of stability testing requirements of ich with otherJun Brown
Stability plays an important role in the drug development process. Present work aims to compare the stability
testing (ST) requirements of International Conference on Harmonization (ICH) with other international regulatory
agencies like World Health Organization (WHO), Association of South East Asian Nations (ASEAN) and
European Agency for Evaluation of Medicinal and Health Products (EMEA). ICH guidelines describe stability
testing requirements for new drug substance and drug product. WHO guidelines describe stability testing
requirements for both new and existing Active pharmaceutical ingredients (APIs) and addresses information
to be submitted in original and subsequent applications for marketing authorization of their related Finished
pharmaceutical products (FPP) for human use. ST requirements for WHO are similar, except for the parameters
like selection of batches and storage conditions. WHO guidelines have an additional requirement for long term
storage condition (general case) and accelerated storage conditions (substance/product intended to be stored
in refrigerator). ASEAN guideline mainly focuses on the requirements for stability testing of drug products along
with new chemical entities (NCE’s). The differences were observed in stress testing, selection of batches and
real time storage conditions. EMEA guidelines discussed here are an extension of the note for guidance on
stability testing requirements for new active substance and related products. It sets out the stability testing
requirements for existing active substance and related finished product. The minimum time period to be covered
by data at the time of submission during long term storage conditions differs from ICH guidelines.
The document discusses International Council for Harmonisation (ICH) guidelines related to stability testing of drug substances and products. It provides an overview of the historical background and development of ICH. It summarizes several ICH guidelines including Q1A on stability testing, Q1B on photostability testing, Q1C on stability testing for new dosage forms, and Q1D on bracketing and matrixing designs for stability testing. It also discusses stability storage conditions, principles of ICH guidelines for stability testing, and the objectives of guidelines like Q1E on evaluation of stability data.
The ICH Q1A guideline provides recommendations for conducting stability studies on drug substances and drug products to establish retest and shelf-life periods. Key points include:
- Stability studies should be conducted on 3 primary batches under long-term, intermediate, and accelerated storage conditions specified in the guideline.
- Testing frequency is typically every 3 months for the first year of long-term studies and specifications cover physical, chemical, biological, and microbiological attributes.
- The purpose is to evaluate how quality varies over time under influence of factors like temperature and humidity and provide evidence to support recommended storage conditions.
1) There are four levels of in vitro-in vivo correlations (IVIVC) ranging from Level A to Level D. Level A correlation involves point-to-point correlation of dissolution and absorption profiles and is most useful for regulatory purposes. Level B uses statistical moments, while Level C correlates single dissolution timepoints to pharmacokinetic parameters.
2) The document discusses a case study developing a Level A IVIVC for a prolonged-release hydrocodone formulation. Dissolution and pharmacokinetic profiles from clinical studies were used to establish a direct correlation between % dissolved and % absorbed using linear and nonlinear time scaling.
3) The Level A IVIVC showed good predictability of less than 10%
This document discusses guidelines for stability testing of pharmaceuticals according to the International Conference on Harmonization (ICH). It describes the ICH guidelines for stability testing, including stability protocols, reports, and studies. The key points covered include stability testing procedures, factors affecting drug stability, types of stability studies, and organizations that regulate stability guidelines such as the ICH.
The document discusses guidelines for conducting stability studies on drug substances and drug products according to ICH guidelines. It provides details on the objectives and scope of stability testing, factors to consider like storage conditions and container closure systems, types of studies to perform, and statistical approaches to analyze the data. The goal is to establish retest periods for drug substances and shelf lives for drug products based on stability data from multiple batches in order to submit this information for product registration applications.
This document summarizes guidelines for stability testing according to ICH guidelines. The key points are:
1) ICH guidelines are most commonly accepted and provide information on stability testing in the EU, Japan, and US. Stability testing aims to provide evidence of how quality varies over time under different conditions.
2) The objectives of ICH are more economical use of resources, eliminating delays in global development and availability of medicines, and maintaining safeguards for quality, safety, and efficacy.
3) Stability topics covered by ICH include testing, validation, impurities, specifications, and manufacturing. This summary focuses on stability testing guidelines for new drug substances and products.
This document provides an overview of the ICH Q1A(R2) guideline for stability testing of new drug substances and products. The guideline defines the stability data package required for drug registration in major regions. It addresses testing timelines and conditions for long term, intermediate, and accelerated studies on at least three batches of drug substance and product. The goal is to establish a re-test period or shelf life and recommended storage conditions. Specifications must cover attributes susceptible to change that could impact quality, safety or efficacy. The guideline provides detailed recommendations for testing frequency, storage conditions, and evaluation of results.
The document discusses ICH stability testing guidelines for drug substances and products, outlining the types of studies required including long term, intermediate, and accelerated studies under various storage conditions. Key aspects that are evaluated include physical, chemical, and microbial changes that may occur over time and factors that influence stability such as temperature, humidity, and light exposure. The purpose of stability testing is to establish a product's shelf life and ensure it remains safe and effective when stored as recommended.
Stability testing of biotechnological/ biological products (Q5C )UshaKhanal3
The document provides guidance on stability testing and data requirements for biotechnological/biological products. It recommends conducting long-term stability studies on at least three batches of the drug substance and drug product under various storage conditions to generate data to establish shelf life. It also discusses the use of representative batches, intermediate stability testing, and specifications for labeling storage conditions.
The document discusses guidelines for stability testing from the International Conference on Harmonisation (ICH). It provides an overview of several ICH guidelines related to stability testing of drug substances and products, including guidelines on photostability testing, new dosage forms, bracketing and matrixing designs, and evaluation of stability data. It also summarizes key aspects of conducting stability studies such as selecting representative batches, appropriate container closure systems, testing frequency and storage conditions, and evaluation of results. Stress testing is discussed as a way to validate analytical methods and identify potential degradants.
This document provides an index of quality, safety, efficacy, and multidisciplinary guidelines created by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The index includes over 50 finalized guidelines organized by topic area and date. It also lists guidelines that have been released for further consultation and development.
The document outlines the key stages and requirements for drug development and approval by the FDA. It discusses the necessary chemical, manufacturing and controls (CMC) information that must be submitted at each stage, including details on the drug substance, manufacturing process, specifications, stability testing and other information for both the drug substance and drug product.
The document summarizes the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) quality guidelines. The ICH brings together regulatory authorities and the pharmaceutical industry to discuss drug registration. The quality guidelines cover topics such as stability testing, validation of analytical procedures, impurities, pharmacopoeias, quality of biotechnological products, specifications, good manufacturing practices, pharmaceutical development, quality risk management, and the pharmaceutical quality system.
Drug stability refers to a drug substance or product remaining within established specifications over time. The stability of a product is expressed as its shelf life or expiry period. Stability testing involves multiple stages from early stress testing to ongoing long-term testing as required by regulatory bodies. Stability is affected by various factors related to the drug, formulation, and environment. Reduced stability study designs like bracketing and matrixing allow testing of representative samples and are acceptable with proper scientific justification.
This document summarizes guidelines from the International Conference on Harmonisation (ICH) regarding stability testing of new drug substances and products. It discusses ICH guidelines Q1A(R2) through Q1F, which provide recommendations on conducting stability studies under various storage conditions to determine appropriate re-test periods and shelf lives. The guidelines specify the types of studies, including stress testing, selection of batches, container closure systems, specifications, testing frequency, and evaluation criteria. The document outlines recommended storage conditions and minimum time periods for long-term, intermediate, and accelerated stability studies to support product registrations.
This document discusses ICH guidelines for stability testing and protocols. It provides an overview of ICH partners and guidelines related to quality, safety, and efficacy. It then focuses on ICH guideline Q1, which provides guidance on stability testing of new active pharmaceutical ingredients and finished pharmaceutical products. Key aspects covered in Q1 include stress testing, selection of batches, storage conditions, container closure systems, and photo stability testing. The document also discusses bracketing and matrixing designs, stability protocols and reports, and requirements for stability results and re-test periods.
Q1E Evaluation of Stability Data by Rahim Khoja presented on December 22, 2014Rahim Khoja
This document provides guidelines for using stability data to propose a retest period or shelf life in product registration. It describes how extrapolation of data beyond the available long-term data can be considered. The guidelines recommend a systematic approach to presenting and evaluating stability data from physical, chemical, biological and microbiological tests. Extrapolation may be proposed if no significant changes are observed under accelerated conditions and it is assumed the same change pattern will continue. A retest period granted via extrapolation should be verified with additional long-term data. The guidelines also provide decision trees and examples of statistical analyses to determine if data from different batches can be pooled for evaluating a single proposed period.
Aims: Dried Blood Spot (DBS) sampling is a frequently used method to obtain Haemoglobin A1C (HbA1c) in clinical studies of freeliving populations. Under controlled conditions, DBS sampling is a valid and robust alternative to traditional Whole Blood (WB) sampling. The objective of this analysis was to investigate the impact of storage conditions on the validity of HbA1c assessed from DBS collected in free-living and to develop a method to correct for this type of error.
The document describes COMPACT, a database for analyzing common eligibility features in clinical trials. It extracts metadata, categorical features, and numeric features from trial summaries on ClinicalTrials.gov using natural language processing. Analysis of Type 2 diabetes trials in COMPACT found common categorical features like diabetes and metformin use. Numeric features like HbA1c levels and BMI were frequently used, often with value ranges of 7.0-10.0% and 25.0-40.0 respectively. The database and a visualization tool called VITTA are resources for understanding trial population design and improving generalizability. Future work includes enhancing feature analysis and comparing trial populations to patient populations.
The document describes COMPACT, a database for analyzing common eligibility features in clinical trials. It extracts metadata, categorical features, and numeric features from trial summaries on ClinicalTrials.gov using natural language processing. Analysis of Type 2 diabetes trials in COMPACT found common categorical features like diabetes and metformin use. Numeric features like HbA1c levels and BMI were frequently used, often with value ranges of 7.0-10.0% and 25.0-40.0 respectively. The database and a visualization tool called VITTA are resources for understanding trial population design and improving transparency of eligibility criteria.
Role of the Biochemistry Labs in Promoting the Health Care Services for the I...IJERA Editor
The health care in the State of Kuwait depends to a greater extent on the biochemical and clinical labs attached
at each hospital. The data obtained from these laboratories will facilitate the process of diagnosing the disease
accurately. This will have a positive impact on the selection of appropriate treatment for the patients in general
and for diabetics specifically.
The main objective of this research was to build a profile for lab analysis and a database for building a
comprehensive system of integrated activities to raise health care for diabetic patients in Kuwait. The study
revealed the burden of admitted diabetic cases on the blood chemistry laboratory in Sabah Hospital (in relation
to length of stay and total numbers of lab requests). The aim was fulfilled by designing a model of the
biochemical tests for diabetics; filling in forms from the reality of patient data, completing and analyzing the
results electronically.
The study showed the importance of biochemical and clinical labs since they act as the link of patient's
information at the secondary health care level.
The document discusses the International Council for Harmonization (ICH), which aims to harmonize technical requirements for pharmaceutical registration globally. It provides an overview of ICH guidelines, focusing on quality (Q) guidelines for stability testing, impurities, and good manufacturing practices. The Q1A guideline on stability testing recommends long-term storage conditions of 12 months at 25°C/60% RH or 30°C/65% RH for 3 primary batches to evaluate product stability over time under various temperature and humidity conditions.
Lot To Lot Variability Of Test Strips And Accuracy Assessment Of Systems Formikezisiss
This study evaluated the lot-to-lot variability between four test strip lots for each of five blood glucose monitoring systems according to ISO 15197 standards. The maximum difference between strip lots for each system ranged from 1.0% to 13.0%. Only two systems met ISO standards with all lots. The study highlights the need for manufacturers to regularly check accuracy between lots to minimize risks of incorrect treatment decisions due to variability.
This document describes the results of an international consensus process to develop management recommendations for infants with an inconclusive diagnosis following newborn cystic fibrosis screening. Experts generated statements through a modified Delphi method. Infants were divided into two groups based on sweat chloride levels and CFTR mutations. After two rounds, consensus was reached on a designation of "CF Screen Positive, Inconclusive Diagnosis" (CFSPID) and on most management statements. This provides guidance for consistent care of these infants with an uncertain diagnosis.
This study assessed the clinical performance and safety of the Space GlucoseControl (SGC) system for blood glucose control in intensive care patients across 17 centers in 9 European countries. The SGC uses an enhanced Model Predictive Control algorithm to advise insulin dosing. Over 500 patients were included, with a median study time of 2.9 days. The SGC achieved a median time in target blood glucose range of 4.4-8.3 mmol/L of 83.0% and a low rate of hypoglycemia. The system's recommendations were followed 99.6% of the time. The SGC demonstrated effective glycemic control across varied clinical settings and nutritional protocols.
This study examined the relationship between apolipoprotein B (apo B) levels and diabetic retinopathy in 168 Egyptian patients with type 2 diabetes. The results showed a statistically significant increase in apo B levels in patients with retinopathy compared to those without. There was also a fair correlation between higher apo B levels and more severe grades of retinopathy. Additionally, patients with diabetic maculopathy had significantly higher apo B levels than those without maculopathy. The study concludes that elevated apo B is associated with retinopathy and macular edema in type 2 diabetes.
This primer is intended for the non-clinician. After reading it, hopefully you will have a slightly better understanding of the complexities of clinical trials.
A1 c versus glucose testing 19 5-2014 departement conferenceMoustafa Rezk
This document compares glucose testing and A1C testing for diagnosing diabetes. Glucose testing has limitations including lack of reproducibility between tests, requirement of fasting, and diurnal variation. A1C testing has advantages like not requiring fasting and less biological variability. However, A1C can be affected by factors like hemoglobinopathies, kidney disease, and alcohol use. Both tests are useful but understanding each test's limitations is important for accurate results. Overall A1C is convenient and detects undiagnosed diabetes but may not be suitable for all patients due to potential interferences. Standardization of A1C assays is also needed.
This document provides guidelines for managing post-meal glucose levels in diabetes. It summarizes the methodology used to develop the guidelines, which included reviewing evidence and reaching consensus among an international panel of experts. The guidelines are an update from 2007 and aim to help lower risks of diabetes complications by achieving optimal post-meal glucose control.
C14 idf guideline for management of postmeal glucose in diabetes 2011Diabetes for all
This document provides guidelines for managing post-meal glucose levels in people with diabetes. It finds that post-meal hyperglycemia is independently associated with several harmful health outcomes. While there is no direct evidence that controlling post-meal glucose improves clinical outcomes, targeting both post-meal and fasting glucose is important for achieving optimal glycemic control. A variety of dietary and pharmacological therapies can effectively lower post-meal plasma glucose. The guideline recommends a post-meal glucose target of 9.0 mmol/l or 160 mg/dl as measured 1-2 hours after a meal through self-monitoring of blood glucose.
PROJECT CAH NEWBORN SCREENING DBS SPECIMEN COLLECTION AND HANDLING dr saras ...RahimiRamli9
The document describes a pilot study to implement newborn screening for Congenital Adrenal Hyperplasia (CAH) in Malaysia. CAH is caused by mutations that impair steroidogenic enzyme activity and can lead to life-threatening issues if not detected early. The study aims to evaluate methods for CAH newborn screening using dried blood spots to measure 17-hydroxyprogesterone levels, establish local population cut-offs, and allow early detection to prevent health issues from an undiagnosed CAH condition.
This study aimed to analyze maternal serum peptides in the early second trimester to identify potential biomarkers for predicting gestational diabetes mellitus (GDM). Serum samples were collected from women at 16-18 weeks of pregnancy and later classified as having GDM or being healthy controls based on later glucose tolerance tests. Peptidomic analysis using liquid chromatography-tandem mass spectrometry identified 297 peptides from 228 proteins that were differentially expressed between GDM and control groups. These peptides may help predict GDM and allow for earlier intervention. The study provides the first validated peptidome profile of early second trimester serum to investigate biomarkers for predicting GDM.
ABSTRACT- Introduction: Importance of measurement of glycated hemoglobin (HbA1c) has been recommended for
the diagnosis of diabetes and pre-diabetes. However, various epidemiological studies conducted different parts of the
universe have shown significant discordance between HbA1c and glucose-based tests. Glycated hemoglobin (HbA1c) is
assumed to be the gold standard for monitoring glycemic control in patients with diabetes mellitus disorder. The Glycated
hemoglobin (HbA1c) assay provided an accurate, precise measure of chronic glycemic levels, and associates with the risk
of diabetes complications.
Materials and Methods: This is a cross sectional prospective study. A total of 868 individuals attended to the medicine
outpatient clinic at Lord Buddha Koshi Medical College, Saharsa, Bihar between Jan 2016 to Dec 2016 were selected for
the study after screening a large cohort visited OPD. The results of FPG, OGTT, and HbA1c for 868 individual were
analyzed as well as all grouped as diabetic patients, glucose intolerant (pre-diabetes) patients, and non-diabetic patients
according to new ADA criteria for the diagnosis of diabetes.
Results: Diagnostic sensitivity of all diabetic criteria were 80.33% for A1c; 75% for OGTT and only 41.87% for FPG
respectively.
Conclusion: The proposed A1c diagnostic criteria have greater diagnostic than FPG and 2-h OGTT regarding a diagnosis
of diabetes mellitus disorder.
Key-words- Glycated Hemoglobin, Fasting Plasma Glucose, Oral glucose tolerances test (OGTT), Diabetes Mellitus,
and Pre- diabetes
This document describes an interlaboratory study conducted by 11 laboratories to evaluate the precision and practicality of a nonaqueous capillary electrophoresis (NACE) method for determining the content of R-timolol impurity in S-timolol maleate samples. The study was designed according to ISO guidelines and involved qualitative and quantitative assessments of the method performances within and between laboratories. Statistical analysis of the results allowed estimation of variances within and between laboratories, days, and replicates to determine the method's repeatability and reproducibility. The estimated measurement uncertainty was found to be concentration-dependent above a certain threshold.
Similar to อ้างอิง 1 standardisation mosca cclm_2007 (20)
A newspaper article discusses affordable universal healthcare and progress towards development goals. It notes that in 2015, the UN adopted goals aiming to provide universal healthcare coverage for all citizens worldwide by 2030. Currently, only about half the world's population has access to essential health services.
The document outlines the budget for HIV/AIDS and TB activities in South Africa for the 2022/2023 fiscal year, including funds for testing, treatment, and case management. It details the budgets for various line items such as laboratory services, drugs and supplies, human resources, and district allocations. The budgets are broken down by funding source and program area with specific grant reference numbers provided.
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ABDOMINAL TRAUMA in pediatrics part one.drhasanrajab
Abdominal trauma in pediatrics refers to injuries or damage to the abdominal organs in children. It can occur due to various causes such as falls, motor vehicle accidents, sports-related injuries, and physical abuse. Children are more vulnerable to abdominal trauma due to their unique anatomical and physiological characteristics. Signs and symptoms include abdominal pain, tenderness, distension, vomiting, and signs of shock. Diagnosis involves physical examination, imaging studies, and laboratory tests. Management depends on the severity and may involve conservative treatment or surgical intervention. Prevention is crucial in reducing the incidence of abdominal trauma in children.
Adhd Medication Shortage Uk - trinexpharmacy.comreignlana06
The UK is currently facing a Adhd Medication Shortage Uk, which has left many patients and their families grappling with uncertainty and frustration. ADHD, or Attention Deficit Hyperactivity Disorder, is a chronic condition that requires consistent medication to manage effectively. This shortage has highlighted the critical role these medications play in the daily lives of those affected by ADHD. Contact : +1 (747) 209 – 3649 E-mail : sales@trinexpharmacy.com
8 Surprising Reasons To Meditate 40 Minutes A Day That Can Change Your Life.pptxHolistified Wellness
We’re talking about Vedic Meditation, a form of meditation that has been around for at least 5,000 years. Back then, the people who lived in the Indus Valley, now known as India and Pakistan, practised meditation as a fundamental part of daily life. This knowledge that has given us yoga and Ayurveda, was known as Veda, hence the name Vedic. And though there are some written records, the practice has been passed down verbally from generation to generation.
Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
Histololgy of Female Reproductive System.pptxAyeshaZaid1
Dive into an in-depth exploration of the histological structure of female reproductive system with this comprehensive lecture. Presented by Dr. Ayesha Irfan, Assistant Professor of Anatomy, this presentation covers the Gross anatomy and functional histology of the female reproductive organs. Ideal for students, educators, and anyone interested in medical science, this lecture provides clear explanations, detailed diagrams, and valuable insights into female reproductive system. Enhance your knowledge and understanding of this essential aspect of human biology.
Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
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TEST BANK For Community Health Nursing A Canadian Perspective, 5th Edition by...Donc Test
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Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
1. Article in press - uncorrected proof
Clin Chem Lab Med 2007;45(8):1077–1080 ᮊ 2007 by Walter de Gruyter • Berlin • New York. DOI 10.1515/CCLM.2007.246 2007/211
Global standardization of glycated hemoglobin
measurement: the position of the IFCC Working Group1),2)
8
International Federation of Clinical Chemistry Center for Disease Control and Prevention, Atlanta,
and Laboratory Medicine (IFCC) GA, US
9
IFCC Scientific Division INSTAND e.V., Dusseldorf, Germany
¨
10
Brigham & Women’s Hospital and Harvard
Working Group on Standardization of HbA1c Medical School, Boston, MA, USA
(WG-HbA1c) 11
Queen Beatrix Hospital, Winterswijk,
The Netherlands
Andrea Mosca1, Ian Goodall2, Tadao Hoshino3,
Jan O. Jeppsson4, W. Garry John5,*, Randie R. Abstract
Little6, Kor Miedema7, Gary L. Myers8, Hans
Reinauer9, David B. Sacks10 and Cas W. The measurement of glycated hemoglobin is central
Weykamp11 in the monitoring of glycemic control in patients with
1
diabetes. There are at least 30 different laboratory
Centre for Metrological Traceability in Laboratory assays commercially available to measure the pro-
Medicine (CIRME), Dept. Science and Biomedical portion of HbA1c in blood. In 1995 the IFCC estab-
Technology, University of Milano, Italy lished a Working Group (IFCC WG-HbA1c) to achieve
2
Austin Health, Heidelberg, Australia international standardization of HbA1c measurement.
3
Institute of Biopathological Medicine, Kanagawa, The main achievements can be summarized as fol-
Japan lows: a) a reference measurement procedure has
4
Malmo University Hospital, Malmo, Sweden
¨ ¨ been established with purified primary calibrators;
5
Norfolk and Norwich University Hospital, School of b) a network of reference laboratories has been devel-
Medicine, Health Policy and Practice, UEA, Norwich, oped worldwide; and c) work has begun on imple-
UK mentation of traceability to the IFCC reference
6
University of Missouri School of Medicine, system. The IFCC WG-HbA1c recognizes the recom-
Columbia, MO, USA mendation of the IFCC-IUPAC Committee on Nomen-
7
Isala Klinieken, Zwolle, The Netherlands clature, Properties and Units that the analyte
measured by the IFCC reference measurement pro-
cedure has been defined as bN1-deoxyfructosyl-
hemoglobin and that the recommended measure-
1)
This position paper was commissioned by the IFCC, but it ment units are mmol/mol. The IFCC WG-HbA1c rec-
does not carry any official IFCC endorsement. ommends maintaining the use of the name HbA1c in
2)
IFCC Sections printed in J. Clin. Chem. Clin. Biochem. are clinical practice.
listed in the Cumulative Index, which appeared in connection Clin Chem Lab Med 2007;45:1077–80.
with the contents of this journal in Volume 27, 1989 and
since 1991 have been printed in (Eur.) J. Clin. Chem. Clin.
Biochem.
Keywords: diabetes; glycated hemoglobin; HbA1c;
IFCC 1991/1 Vol. 29, 435–457 network; reference methods; standardization.
IFCC 1991/2 Vol. 29, 531–535
IFCC 1991/3 Vol. 29, 577–586
IFCC 1991/4 Vol. 29, 767–772 Background
IFCC 1992/1 Vol. 30, 901–905
IFCC 1994/1 Vol. 32, 639–655
The measurement of glycated hemoglobin (HbA1c;
IFCC 1995/1 Vol. 33, 247–253
IFCC 1995/2 Vol. 33, 399–404
bN1-deoxyfructosyl-hemoglobin) is frequently used in
IFCC 1995/3 Vol. 33, 623–625 diabetes management to monitor mid- to long-term
IFCC 1995/4 Vol. 33, 627–636 glycemic control and to assess the risk of develop-
IFCC 1995/5 Vol. 33, 637–660 ment of diabetic complications in patients with dia-
IFCC 1997/1 Vol. 35, 317–344 betes (1, 2). A level ‘‘A’’ recommendation in the 2002
IFCC 1997/2 Vol. 35, 345–349 guidelines by the US National Academy of Clinical
IFCC 1997/3 Vol. 35, 805–831
Biochemistry (NACB) emphasizes these issues, also
IFCC 1997/4 Vol. 35, 833–843
For IFCC sections printed in Clin. Chem. Lab. Med. since stating that treatment goals have to be based on the
1998, please visit the link http://degruyter.com/journals/ results of retrospective clinical trials, such as the Dia-
extenza, where they are freely accessible. betes Control and Complications Trial (DCCT) and UK
*Corresponding author: Dr. W. Garry John, Norfolk and Prospective Diabetes Study (UKPDS) (3, 4).
Norwich University Hospital, School of Medicine, Health
At present at least 30 different laboratory methods
Policy and Practice, UEA, Norwich, UK
E-mail: g.john@nnuh.nhs.uk are commercially available to measure the proportion
Received for publication May 7, 2007 of HbA1c in blood. A recent review on this topic has
2. Article in press - uncorrected proof
1078 Mosca et al.: Global standardization of HbA1c measurement
been published by John (5). There are a number of rules for the certification of reference values and
published reports relating to between-laboratory and for the calculation of the uncertainties of the cal-
between-method agreement for HbA1c, much of this ibrators (19, 20).
information coming from National External Quality d) Several comparison studies have been performed
Assessment Schemes (EQAS) (6–12). In the United between the IFCC reference measurement labo-
States, as well as in several other countries, partici- ratories and the existing DCMs. These studies
pation in proficiency testing is mandatory. Based on found stable relationships between the IFCC and
one large proficiency survey (College of American different DCM systems and the corresponding
Pathologists GH2 survey), more than 99% of the labo- regression equations (the ‘‘master equations’’)
ratories in the US use a method that is aligned to the were published (21).
National Glycohemoglobin Standardization Program e) Secondary reference materials have been pro-
(NGSP) (13). In addition to the Designated Compari- duced in the form of panels of fresh and frozen
son Method (DCM) developed by the NGSP, other whole blood and distributed to the manufacturers
DCMs have been developed in Sweden and in Japan. and to laboratories performing DCMs to anchor
It is beyond the scope of the present paper to analyze their methods to the IFCC reference system.
the performance of different methods. However, data
obtained from the above studies demonstrate that Figure 1 displays the IFCC reference system and the
standardization of HbA1c methods between labora- traceability chain for HbA1c.
tories is still an important issue. Indeed, interlabora-
tory variability of 5%–7% (expressed as CV) has been
shown for HbA1c values between 6% and 10% HbA1c Current issues
(% of total Hb). Poor between-laboratory agreement
can also be found when laboratories are using the Traceability to the IFCC reference system for HbA1c
same manufacturer’s method, although some manu- has not been implemented because concern has been
facturers display between-laboratory agreement as expressed about the impact that changes in HbA1c
low as 3%. values may have on patient care (22–24). Criticisms
are related to the fact that the IFCC reference meas-
urement procedure gives HbA1c values numerically
The IFCC program for HbA1c standardization lower (–1.3% to –1.9% across the pathophysiological
range) than those obtained by the DCMs and NGSP-
In 1995 the IFCC established a Working Group (IFCC aligned methods. This finding has generated signifi-
WG-HbA1c) to achieve international standardization cant debate on how HbA1c should be reported.
of HbA1c measurement (14). The activities achieved From the beginning of 2004, another group dealing
by this WG so far can be summarized as follows: with the topic of harmonizing HbA1c assays has been
established among three clinical societies: the Ameri-
a) Highly purified HbA1c and HbA0 materials have
can Diabetes Association (ADA), the European Asso-
been produced (15), and these have been made
ciation for the Study of Diabetes (EASD) and the Inter-
available to the 14 laboratories of the IFCC net-
national Diabetes Federation (IDF). The decisions that
work (see below). These primary reference mate-
this team of experts has reached so far have been
rials will be available in 2007 through the Institute
published (24) and can be summarized as follows:
for Reference Materials and Measurements
(IRMM) (identification codes 466 and 467, 1. Adopt the IFCC reference measurement procedure
respectively). as the new global standard for calibration of
b) A reference measurement procedure for HbA1c HbA1c assays by manufacturers.
has been developed (16). This method is based on 2. Use the new IFCC methodology to anchor an
the proteolytic digestion of red cell hemoglobins ‘‘international certification process’’ within the
followed by quantitative peptide mapping by existing international laboratory networks. The
HPLC-mass spectrometry or HPLC-capillary elec- ADA/EASD/IDF group did not elaborate on this
trophoresis. It has been voted on by the National statement. Currently the IFCC network of refer-
Societies affiliated to the IFCC and published as ence laboratories is anchoring the other DCM net-
an ‘‘approved IFCC reference measurement pro- works (the NGSP network in the US and the
cedure’’ (17). networks in Sweden and in Japan). This is actu-
c) A network of reference measurement laboratories ally carried out through the exercises of the net-
has been implemented. Two experiments are per- work, in which the WG-HbA1c has been able to
formed every year, in which materials are distri- monitor the stability of the master equations pre-
buted to the laboratories for comparison viously published (21).
purposes, and also to assign HbA1c values to can- 3. Manufacturers/laboratories should not change the
didate calibrators and controls. These studies HbA1c values reported until further work has been
have been performed since 1999 and have also completed, i.e., DCCT/UKPDS numbers and
been important in refining the reference measure- derived decision limits will continue to be used.
ment procedure, which is regularly updated as Further work refers to the studies designed to
soon as new technical information becomes avail- investigate the relationship between HbA1c and
able (18). The network has developed a set of mean blood glucose (MBG).
3. Article in press - uncorrected proof
Mosca et al.: Global standardization of HbA1c measurement 1079
Figure 1 IFCC reference measurement system and traceability chain for HbA1c.
4. Following completion of the ongoing clinical tri- this nomenclature when used to describe the analyte
als, if the relationship between HbA1c and MBG measured by the IFCC reference measurement pro-
is sufficiently defined and constant in different cedure. The IFCC WG-HbA1c believes that this term
populations worldwide, HbA1c could be reported cannot be used to describe the fraction measured by
as MBG. routine clinical methods; these methods, even though
traceable to the IFCC reference measurement proce-
Until now, the IFCC WG-HbA1c has not taken an offi- dure, do not specifically measure the fraction reflect-
cial position on definitive implementation of trace- ing glycation at the N-terminal valine on the b-chains
ability to the IFCC reference system for HbA1c, nor of the hemoglobin molecule. In addition, the IFCC
has it expressed an opinion on possible endorsement WG-HbA1c does not agree to the use of DOF-Hb in
of the document published by the ADA/EASD/IDF clinical practice and recommends that the abbrevia-
Working Group (24). The present document, there- tion ‘‘HbA1c’’ remains as long as the measurands of
fore, serves to express the IFCC WG-HbA1c position routine clinical methods remain unchanged. With
on this issue. regard to the measurement units and numerical value
expressed in IFCC numbers, to avoid confusion
among healthcare personnel and patients, the meas-
Name and units for the IFCC standardized urement unit ‘‘millimole per mole’’ will be chosen
HbA1c test instead of ‘‘percent’’ (%).
The IFCC WG-HbA1c does not support the concept
Recently, a recommendation by the IFCC-IUPAC Com- of reporting HbA1c only as ‘‘mean blood glucose’’
mittee on Nomenclature, Properties and Units (24).
(C-NPU) has been prepared that relates to the system-
atic name and units for HbA1c as measured by the
IFCC reference measurement procedure. This IFCC- How to move to the IFCC values for HbA1c
IUPAC document has been approved by the National
Societies affiliated to the IFCC and is published in this When introducing a new analytical system or a new
issue of the journal as an IFCC recommendation (25). method of reporting results, it is important that this is
Briefly, the C-NPU proposes that the term for indi- done in a planned way. This is especially true if the
cating the fraction of the b-chains of hemoglobin that change may impact patient care. It is crucial if HbA1c
has a stable hexose adduct on the N-terminal amino values are changed that there is thorough planning
acid valine may be expressed as ‘‘Hemoglobin beta and preparation of literature that informs clinicians,
chain(Blood)—N-(1-deoxyfructos-1-yl)hemoglobin beta patients and laboratories about the new way of
chain’’. In the IFCC-IUPAC document it is recommend- reporting HbA1c results. It will be necessary to pre-
ed that this term be used to describe the measurand pare documents so that the crucial information col-
of the IFCC reference measurement procedure, and lected up to now (for instance, data from large clinical
that this can be shortened in ‘‘everyday speech’’ to trials such as the DCCT and UKPDS) is not lost when
DOF-Hb. The IFCC WG-HbA1c agrees with the use of expressing HbA1c in the new IFCC standardized val-
4. Article in press - uncorrected proof
1080 Mosca et al.: Global standardization of HbA1c measurement
ues. It is difficult to estimate in advance how long this 9. http://www.equalis.se/. Accessed June 21, 2007.
phase will be, but probably at least 1 year is needed. 10. http://www.instand-ev.de/. Accessed June 21, 2007.
11. http://www.glicata.org/. Accessed June 21, 2007.
It also seems advisable to consider the results of
12. http://www.rcpaqap.com.au. Accessed June 21, 2007.
the EASD/ADA/IDF study evaluating the relationship
13. http://www.ngsp.org. Accessed June 21, 2007.
between HbA1c and MBG. When this trial is complete, 14. Hoelzel W, Miedema K. Development of a reference sys-
it will be necessary to define acceptability limits for tem for the international standardisation of HbA1c/glyco-
this relationship for implementing estimation of MBG hemoglobin determinations. J Int Fed Clin Chem 1996;
from the measurement of HbA1c. To this end, the 9:62–7.
IFCC WG-HbA1c is available to collaborate with the 15. Finke A, Kobold U, Hoelzel W, Weycamp C, Jeppsson
above-mentioned Societies in such work. If the cor- JO, Miedema K. Preparation of a candidate primary ref-
erence material for the international standardisation of
relation between HbA1c and MBG is sufficiently close
HbA1c determinations. Clin Chem Lab Med 1998;36:
to the selected limits, then reporting of an estimated 299–308.
MBG (eMBG), using a mathematical formula based on 16. Kobold U, Jeppsson JO, Dulffer Th, Finke A, Hoelzel W,
¨
the IFCC standardized HbA1c value, together with the Miedema K. Candidate reference method for HbA1c
HbA1c value itself, will be possible. The final results based on peptide mapping. Clin Chem 1997;43:1944–51.
of the study are expected in December 2007. 17. Jeppsson JO, Kobold U, Barr J, Finke A, Hoelzel W, Hos-
hino T, et al. Approved IFCC reference method for the
measurement of HbA1c in human blood. Clin Chem Lab
Med 2002;40:78–89.
References 18. http://www.ifcchba1c.net/. Accessed June 21, 2007.
19. Konnert A, Berding C, Arends S, Parvin C, Rohlfing CL,
1. Sacks DB, Bruns DE, Goldstein DE, Maclaren NK, Mc- Wiedmeyer HM, et al. Statistical rules for laboratory net-
Donald JM, Parrott M. Guidelines and recommendations works. J Test Eval 2006;34:1–7.
for laboratory analysis and management of diabetes mel- 20. Konnert A, Arends S, Schubert S, Berding C, Weykamp
litus. Clin Chem 2002;48:436–72. C, Siebelder C. Uncertainty calculation for calibrators of
2. American Diabetes Association. Standards of medical the IFCC HbA1c standardization network. Accred Qual
care in diabetes. Diabetes Care 2004;27(Suppl 1):S15–35. Assur 2006;11:316–28.
3. DCCT Research Group. The effect of intensive treatment 21. Hoelzel W, Weykamp C, Jeppsson JO, Miedema K, Barr
of diabetes on the development and progression of long- JR, Goodall I, et al. IFCC reference system for measure-
term complications in insulin-dependent diabetes melli- ment of hemoglobin A1c in human blood and the nation-
tus. N Engl J Med 1993;329:977–86. al standardization schemes in the United States, Japan,
4. UK Prospective Diabetes Study (UKPDS) Group. Intensive and Sweden: a method-comparison study. Clin Chem
blood glucose control with sulphonylureas or insulin 2004;50:166–74.
compared with conventional treatment and risk of com- 22. Hanas R. Psychological impact of changing the scale of
plications in patients with type 2 diabetes (UKPDS 33). reported HbA1c results affects metabolic control. Diabe-
Lancet 1998;352:837–53. tes Care 2002;25:2110–1.
5. John WG. Haemoglobin A1c: analysis and standardisation. 23. Home P. Standardisation of glycated haemoglobin. Br
Clin Chem Lab Med 2003;41:1199–212. Med J 2004;329:1196–7.
6. http://www.ukneqas.org.uk/. Accessed June 21, 2007. 24. Sacks DB for the ADA/EASD/IDF Working group for the
7. http://www.euroreflab.com/. Accessed June 21, 2007. HbA1c Assay. Global harmonization of hemoglobin A1c.
8. Valdiguie P, de Graeve J, Corberand JX, Fernet Clin Chem 2005;51:681–3.
P. 20 years of quality control in clinical laboratories. Ann 25. Nordin G, Dybkaer R. Recommendation for term and
Biol Clin 2000;58:659–61 (www.ctcb.com. Accessed June measurement unit for ‘‘HbA1c’’. Clin Chem Lab Med
21, 2007). 2007;45:1081–2.