This document provides an overview of stability principles and case studies for APIs and FPPs. Some key points include:
1) The purpose of stability testing is to provide evidence of how quality varies over time under different environmental factors like temperature, humidity, and light. It also studies the impact of product-related factors.
2) Stress testing identifies likely degradation products and pathways. It is done on a single API batch under conditions like heat, humidity, light, and acid/base to cause 10-30% degradation.
3) For FPPs, light testing is only required if the API or packaging are not light stable. Otherwise, stating "protect from light" on labeling is sufficient if the container
Stability testing is conducted to provide evidence on how the quality of a drug substance or product varies over time under the influence of environmental factors like temperature and humidity. It helps establish a re-test period or shelf life and recommended storage conditions. Stress testing involves subjecting samples to more extreme conditions to identify potential degradants and validate stability-indicating methods. Protocols specify batches tested, storage conditions, tests conducted, and timepoints. ICH guidelines provide recommendations for stability testing conditions and acceptance criteria.
The document discusses stability testing of drug substances and products. Stability testing aims to provide evidence of how a drug's quality changes over time under various environmental factors like temperature, humidity and light. It helps establish a re-test period or shelf life for the drug and recommended storage conditions. Key aspects covered include selection of batches, testing frequency and storage conditions for long-term, intermediate and accelerated stability studies as per ICH Q1A guidelines. Specifications include attributes tested and acceptance criteria.
This document discusses guidelines from the International Council for Harmonisation (ICH) for stability testing of drug substances and products. It provides guidance on topics such as the need for harmonized stability testing, types of stability testing, selection of batches and storage conditions for testing, and evaluation of stability data. The guidelines aim to establish a systematic approach to stability testing to ensure quality, safety and efficacy over a product's shelf life and recommend conditions for testing drug substances intended for various storage conditions.
This document summarizes key ICH guidelines related to quality and stability testing. It defines key terms like drug substance, dosage form, drug product, and finished pharmaceutical product. It describes the types of studies conducted for drug substances and products under various storage conditions to establish shelf life and re-test periods. These include long term, intermediate, and accelerated studies. It also summarizes ICH guidelines on specific topics like stability testing (Q1A-Q1F), validation of analytical procedures (Q2), impurities (Q3A-Q3C), and others.
This document discusses drug stability and stability testing. It provides an overview of the objectives, scope, rationale and variables affecting drug stability. It also describes the adverse effects of drug instability and outlines the ICH guidelines for stability testing. Key aspects covered include stress testing, storage conditions for long-term, intermediate and accelerated studies, selection of batches, and container closure systems. The document emphasizes the importance of stability testing in establishing shelf-life and recommended storage conditions for drug products.
Q1A(R2): STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTSBhaumik Bavishi
The document provides guidelines for submitting stability data for drug substances and drug products as part of a registration application. It outlines the objectives, scope, and general principles of stability testing. Guidelines are given for conducting long-term, accelerated, and intermediate stability studies under various storage conditions. Specifications, testing frequency, number of batches, and container closure systems are also addressed. A commitment to continuing stability studies is recommended if the available data does not cover the proposed shelf life period.
1. This document summarizes guidelines for conducting stability studies on drug products and substances according to ICH recommendations. It discusses factors that affect drug stability like temperature, humidity and light. 2. The guidelines describe long term, accelerated and intermediate testing conditions specified by ICH for different climate zones. They also provide examples of accelerated stability testing methods for formulations like emulsions, suspensions and tablets. 3. The document stresses the importance of summarizing stability study results and proposing a shelf life and storage conditions based on the data collected over time.
The document discusses the purpose and types of stability studies for pharmaceutical products. It defines stability as the capability of a formulation to remain within specifications for identity, purity, quality and strength throughout its defined shelf life under recommended storage conditions. The main types of stability are chemical, physical, microbiological, therapeutic and toxicological. Stability testing aims to provide evidence of how quality varies over time under environmental factors like temperature, humidity and light. It also addresses product-related factors like interactions. Protocols, results and conclusions from stability studies should be summarized in the dossier. Ongoing stability programs are required to monitor products throughout their shelf life.
Stability testing is conducted to provide evidence on how the quality of a drug substance or product varies over time under the influence of environmental factors like temperature and humidity. It helps establish a re-test period or shelf life and recommended storage conditions. Stress testing involves subjecting samples to more extreme conditions to identify potential degradants and validate stability-indicating methods. Protocols specify batches tested, storage conditions, tests conducted, and timepoints. ICH guidelines provide recommendations for stability testing conditions and acceptance criteria.
The document discusses stability testing of drug substances and products. Stability testing aims to provide evidence of how a drug's quality changes over time under various environmental factors like temperature, humidity and light. It helps establish a re-test period or shelf life for the drug and recommended storage conditions. Key aspects covered include selection of batches, testing frequency and storage conditions for long-term, intermediate and accelerated stability studies as per ICH Q1A guidelines. Specifications include attributes tested and acceptance criteria.
This document discusses guidelines from the International Council for Harmonisation (ICH) for stability testing of drug substances and products. It provides guidance on topics such as the need for harmonized stability testing, types of stability testing, selection of batches and storage conditions for testing, and evaluation of stability data. The guidelines aim to establish a systematic approach to stability testing to ensure quality, safety and efficacy over a product's shelf life and recommend conditions for testing drug substances intended for various storage conditions.
This document summarizes key ICH guidelines related to quality and stability testing. It defines key terms like drug substance, dosage form, drug product, and finished pharmaceutical product. It describes the types of studies conducted for drug substances and products under various storage conditions to establish shelf life and re-test periods. These include long term, intermediate, and accelerated studies. It also summarizes ICH guidelines on specific topics like stability testing (Q1A-Q1F), validation of analytical procedures (Q2), impurities (Q3A-Q3C), and others.
This document discusses drug stability and stability testing. It provides an overview of the objectives, scope, rationale and variables affecting drug stability. It also describes the adverse effects of drug instability and outlines the ICH guidelines for stability testing. Key aspects covered include stress testing, storage conditions for long-term, intermediate and accelerated studies, selection of batches, and container closure systems. The document emphasizes the importance of stability testing in establishing shelf-life and recommended storage conditions for drug products.
Q1A(R2): STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTSBhaumik Bavishi
The document provides guidelines for submitting stability data for drug substances and drug products as part of a registration application. It outlines the objectives, scope, and general principles of stability testing. Guidelines are given for conducting long-term, accelerated, and intermediate stability studies under various storage conditions. Specifications, testing frequency, number of batches, and container closure systems are also addressed. A commitment to continuing stability studies is recommended if the available data does not cover the proposed shelf life period.
1. This document summarizes guidelines for conducting stability studies on drug products and substances according to ICH recommendations. It discusses factors that affect drug stability like temperature, humidity and light. 2. The guidelines describe long term, accelerated and intermediate testing conditions specified by ICH for different climate zones. They also provide examples of accelerated stability testing methods for formulations like emulsions, suspensions and tablets. 3. The document stresses the importance of summarizing stability study results and proposing a shelf life and storage conditions based on the data collected over time.
The document discusses the purpose and types of stability studies for pharmaceutical products. It defines stability as the capability of a formulation to remain within specifications for identity, purity, quality and strength throughout its defined shelf life under recommended storage conditions. The main types of stability are chemical, physical, microbiological, therapeutic and toxicological. Stability testing aims to provide evidence of how quality varies over time under environmental factors like temperature, humidity and light. It also addresses product-related factors like interactions. Protocols, results and conclusions from stability studies should be summarized in the dossier. Ongoing stability programs are required to monitor products throughout their shelf life.
ICH Guideline Stability Testing of New Drug Substances and Product Q1A(R2).pptxTrishala Bhatt
This presentation outlines the ICH Guideline for Stability Testing of New Drug Substances and Products, Q1A(R2). It serves as a comprehensive framework for ensuring the stability of new pharmaceuticals, with a focus on the requirements for registration applications within the EC, Japan, and the United States. The guideline emphasizes a balance between a standardized approach and the flexibility to adapt to specific scientific considerations and characteristics of the materials under evaluation.
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.
This document discusses ICH guidelines for stability testing and protocols. It provides an overview of the ICH partners that develop guidelines and describes some of the key ICH guidelines related to quality, safety, and efficacy. It then focuses on ICH guideline Q1 which provides recommendations for stability testing of new active pharmaceutical ingredients and finished pharmaceutical products, including stress testing, selection of batches, storage conditions, and photo stability testing. The document also discusses bracketing and matrixing designs for stability testing and outlines what should be included in a stability protocol and report.
This document provides an overview of stability testing for finished pharmaceutical products (FPPs). It discusses stress testing, selection of batches, storage conditions, testing frequency, evaluation of results, and commitments required when stability data does not cover the proposed shelf life. The key aspects covered include conducting studies under long-term, accelerated, and intermediate conditions; evaluating parameters like assay, degradation products, and physical attributes; establishing a shelf life and storage statement; and committing to ongoing stability testing to monitor future batches.
This document summarizes guidelines for stability testing of biological and biotechnological products according to ICH guidelines. It discusses factors that affect stability, types of stability testing, storage conditions, and testing frequency. The key points are that stability testing must demonstrate a product's identity, purity, and potency remain within specified limits during its proposed shelf life under various storage conditions, and that testing should include real-time studies and may involve accelerated or stress conditions to establish an expiration date.
The document provides an overview of stability studies in the pharmaceutical industry. It defines stability as the ability of a substance to remain unchanged over time under specified storage and use conditions. The purpose of stability testing is to provide evidence on drug quality and define shelf life by permitting establishment of storage conditions, retest periods and labeling. Guidelines for stability testing are set by the International Conference on Harmonization (ICH). Stability studies must be conducted on multiple batches under long term, intermediate and accelerated conditions to evaluate the effect of time and various climatic factors on products. Data is used to establish shelf life or retest dates by extrapolation. Labeling must include any special storage instructions.
This document discusses stability studies of a finished pharmaceutical product (FPP) by Zafar Mahmood. It defines the purpose of stability testing as providing evidence of how quality varies over time under various environmental factors like temperature and humidity. This helps establish a product's shelf life and recommended storage conditions. The document outlines types of stability studies including real-time, intermediate, and accelerated studies conducted under different climatic zones and temperatures. It provides guidance on selecting batches, container closure systems, specifications, testing frequency, storage conditions, evaluation, and ongoing stability programs to ensure product quality over time.
This document discusses stability studies and testing. Stability studies are conducted to provide evidence on how the quality of a drug substance or product varies over time under the influence of environmental factors like temperature, humidity, and light. They are required to recommend storage conditions, establish retest and shelf life periods, review product quality, and meet regulatory requirements. Key aspects covered include guidelines for stability testing, types of studies (long term, intermediate, accelerated), storage conditions, specifications, testing frequency, and requirements for stability protocols, batches, and reports.
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.
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 summarizes guidelines for stability testing of biotechnological and biological products. It discusses factors that can affect stability, including temperature, humidity, light and container materials. The guidelines specify conducting real-time stability studies at the proposed storage temperature and testing potency, purity and degradation over time. Manufacturers must propose a stability-indicating profile and validate methods to detect any changes to the identity, purity or potency of the product.
This document summarizes the presentation of ICH stability testing guidelines for new drug substances and products. It discusses the objectives, scope, general principles and guidelines for conducting stability testing of drug substances and products. The key aspects covered include selection of batches, container closure systems, specifications, testing frequency and storage conditions for long term, intermediate and accelerated stability studies. The goals of stability testing are to provide evidence of quality changes over time and establish re-test or shelf life periods under various environmental conditions.
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 document discusses guidelines for stability studies and testing according to ICH. It provides an overview of different types of stability studies including real time testing, accelerated stability testing, and retained sample stability testing. The key guidelines discussed are ICH Q1A, Q1B, Q1C which provide recommendations on stability testing of drug substances, products, and dosage forms. The document also discusses parameters to evaluate stability like potency, purity and molecular characterization as well as factors like storage conditions and temperatures for biological products.
This document provides an overview of stability studies, including the basic concepts, objectives, factors affecting stability, types of stability studies, ICH guidelines, climatic zones, steps for stability testing, and a reference. It defines stability as a drug substance or product retaining its properties and characteristics within specifications for a given time period. The objectives of stability testing are to determine shelf life and storage conditions, ensure formulation and packaging adequacy, understand quality variations over time, and prevent recalls. ICH guidelines cover testing requirements. Studies include long-term, accelerated, and intermediate testing under various climatic zone storage conditions.
The document provides an overview of stability testing during product development. It discusses the importance of stability testing to ensure product quality and safety over the shelf life. Various methods of stability testing are described, including real-time, accelerated, and retained sample testing. Guidelines for stability testing from ICH, WHO, and other agencies are also covered. The document outlines the key aspects of a stability testing protocol, including batches, containers, storage conditions, sampling plan, test parameters, and acceptance criteria. It provides details on conducting, recording, and presenting stability testing data.
This document discusses ICH quality guidelines related to stability testing of drug substances and products. It provides an overview of ICH guidelines Q1A through Q1F which address topics like stability testing conditions and timepoints, evaluation of stability data, photostability testing, bracketing and matrixing designs. Specific details are covered for the drug substance and product such as selection of batches, container closure systems, specifications and labeling. The guidelines provide recommendations for conducting stability studies under long term, intermediate and accelerated storage conditions.
This document discusses stability testing of pharmaceutical products. It states that stability testing involves complex procedures to ensure quality, efficacy and safety of drug formulations. The most important developmental steps are pharmaceutical analysis and stability studies to determine identity, potency and safety. Stability testing provides evidence of how drug quality changes over time and is used to establish shelf life and storage conditions. It discusses various types of stability studies including real-time, accelerated and cyclic temperature stress testing. The document also outlines the guidelines for stability testing protocols.
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.
- Video recording of this lecture in English language: https://youtu.be/Pt1nA32sdHQ
- Video recording of this lecture in Arabic language: https://youtu.be/uFdc9F0rlP0
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
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ICH Guideline Stability Testing of New Drug Substances and Product Q1A(R2).pptxTrishala Bhatt
This presentation outlines the ICH Guideline for Stability Testing of New Drug Substances and Products, Q1A(R2). It serves as a comprehensive framework for ensuring the stability of new pharmaceuticals, with a focus on the requirements for registration applications within the EC, Japan, and the United States. The guideline emphasizes a balance between a standardized approach and the flexibility to adapt to specific scientific considerations and characteristics of the materials under evaluation.
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.
This document discusses ICH guidelines for stability testing and protocols. It provides an overview of the ICH partners that develop guidelines and describes some of the key ICH guidelines related to quality, safety, and efficacy. It then focuses on ICH guideline Q1 which provides recommendations for stability testing of new active pharmaceutical ingredients and finished pharmaceutical products, including stress testing, selection of batches, storage conditions, and photo stability testing. The document also discusses bracketing and matrixing designs for stability testing and outlines what should be included in a stability protocol and report.
This document provides an overview of stability testing for finished pharmaceutical products (FPPs). It discusses stress testing, selection of batches, storage conditions, testing frequency, evaluation of results, and commitments required when stability data does not cover the proposed shelf life. The key aspects covered include conducting studies under long-term, accelerated, and intermediate conditions; evaluating parameters like assay, degradation products, and physical attributes; establishing a shelf life and storage statement; and committing to ongoing stability testing to monitor future batches.
This document summarizes guidelines for stability testing of biological and biotechnological products according to ICH guidelines. It discusses factors that affect stability, types of stability testing, storage conditions, and testing frequency. The key points are that stability testing must demonstrate a product's identity, purity, and potency remain within specified limits during its proposed shelf life under various storage conditions, and that testing should include real-time studies and may involve accelerated or stress conditions to establish an expiration date.
The document provides an overview of stability studies in the pharmaceutical industry. It defines stability as the ability of a substance to remain unchanged over time under specified storage and use conditions. The purpose of stability testing is to provide evidence on drug quality and define shelf life by permitting establishment of storage conditions, retest periods and labeling. Guidelines for stability testing are set by the International Conference on Harmonization (ICH). Stability studies must be conducted on multiple batches under long term, intermediate and accelerated conditions to evaluate the effect of time and various climatic factors on products. Data is used to establish shelf life or retest dates by extrapolation. Labeling must include any special storage instructions.
This document discusses stability studies of a finished pharmaceutical product (FPP) by Zafar Mahmood. It defines the purpose of stability testing as providing evidence of how quality varies over time under various environmental factors like temperature and humidity. This helps establish a product's shelf life and recommended storage conditions. The document outlines types of stability studies including real-time, intermediate, and accelerated studies conducted under different climatic zones and temperatures. It provides guidance on selecting batches, container closure systems, specifications, testing frequency, storage conditions, evaluation, and ongoing stability programs to ensure product quality over time.
This document discusses stability studies and testing. Stability studies are conducted to provide evidence on how the quality of a drug substance or product varies over time under the influence of environmental factors like temperature, humidity, and light. They are required to recommend storage conditions, establish retest and shelf life periods, review product quality, and meet regulatory requirements. Key aspects covered include guidelines for stability testing, types of studies (long term, intermediate, accelerated), storage conditions, specifications, testing frequency, and requirements for stability protocols, batches, and reports.
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.
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 summarizes guidelines for stability testing of biotechnological and biological products. It discusses factors that can affect stability, including temperature, humidity, light and container materials. The guidelines specify conducting real-time stability studies at the proposed storage temperature and testing potency, purity and degradation over time. Manufacturers must propose a stability-indicating profile and validate methods to detect any changes to the identity, purity or potency of the product.
This document summarizes the presentation of ICH stability testing guidelines for new drug substances and products. It discusses the objectives, scope, general principles and guidelines for conducting stability testing of drug substances and products. The key aspects covered include selection of batches, container closure systems, specifications, testing frequency and storage conditions for long term, intermediate and accelerated stability studies. The goals of stability testing are to provide evidence of quality changes over time and establish re-test or shelf life periods under various environmental conditions.
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 document discusses guidelines for stability studies and testing according to ICH. It provides an overview of different types of stability studies including real time testing, accelerated stability testing, and retained sample stability testing. The key guidelines discussed are ICH Q1A, Q1B, Q1C which provide recommendations on stability testing of drug substances, products, and dosage forms. The document also discusses parameters to evaluate stability like potency, purity and molecular characterization as well as factors like storage conditions and temperatures for biological products.
This document provides an overview of stability studies, including the basic concepts, objectives, factors affecting stability, types of stability studies, ICH guidelines, climatic zones, steps for stability testing, and a reference. It defines stability as a drug substance or product retaining its properties and characteristics within specifications for a given time period. The objectives of stability testing are to determine shelf life and storage conditions, ensure formulation and packaging adequacy, understand quality variations over time, and prevent recalls. ICH guidelines cover testing requirements. Studies include long-term, accelerated, and intermediate testing under various climatic zone storage conditions.
The document provides an overview of stability testing during product development. It discusses the importance of stability testing to ensure product quality and safety over the shelf life. Various methods of stability testing are described, including real-time, accelerated, and retained sample testing. Guidelines for stability testing from ICH, WHO, and other agencies are also covered. The document outlines the key aspects of a stability testing protocol, including batches, containers, storage conditions, sampling plan, test parameters, and acceptance criteria. It provides details on conducting, recording, and presenting stability testing data.
This document discusses ICH quality guidelines related to stability testing of drug substances and products. It provides an overview of ICH guidelines Q1A through Q1F which address topics like stability testing conditions and timepoints, evaluation of stability data, photostability testing, bracketing and matrixing designs. Specific details are covered for the drug substance and product such as selection of batches, container closure systems, specifications and labeling. The guidelines provide recommendations for conducting stability studies under long term, intermediate and accelerated storage conditions.
This document discusses stability testing of pharmaceutical products. It states that stability testing involves complex procedures to ensure quality, efficacy and safety of drug formulations. The most important developmental steps are pharmaceutical analysis and stability studies to determine identity, potency and safety. Stability testing provides evidence of how drug quality changes over time and is used to establish shelf life and storage conditions. It discusses various types of stability studies including real-time, accelerated and cyclic temperature stress testing. The document also outlines the guidelines for stability testing protocols.
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.
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- Video recording of this lecture in English language: https://youtu.be/Pt1nA32sdHQ
- Video recording of this lecture in Arabic language: https://youtu.be/uFdc9F0rlP0
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
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1. Stability Principles and Case Studies:
Active Pharmaceutical Ingredient (API)
and
Finished Pharmaceutical Product
(FPP)
Gabriel K. Kaddu
WHO Prequalification of Medicines Programme
Assessment training, Copenhagen
May 2014
1
2. Overview
• Purpose of stability
• Section 2.3.S.7.1(a)/ 2.3.P.8.1(a): Stress Testing
• Section 2.3.S.7.2/ 2.3.P.8.2: Post approval Stability
commitments
• Storage conditions
• Section 2.3.S.7.3/ 2.3.P.8.3: Stability Data
• Stability data
• Other stability studies
• Assessment Tips
2
3. Purpose of stability
• the purpose of stability testing is to: “provide evidence of
how the quality of an API or FPP varies with time under
the influence of a variety of environmental factors such
as temperature, humidity and light.”
• The stability programme also includes the study of
product related factors that influence the quality of the
API or FPP, for example, interaction of API with
excipients, container-closure systems and packaging
materials.
3
4. API- 2.3.S.7.1 (a):
Summary of stress testing
• Stress testing: can help identify the likely degradation
products which, in turn, can help to
• establish the degradation pathways and the intrinsic
stability of the molecule
• and validate the stability-indicating power of the
analytical procedures used.
• Stress testing may be carried out on a single batch of the
API
4
5. API- 2.3.S.7.1 (a):
Summary of stress testing
• The objective of stress testing is not to completely
degrade the API but to cause degradation to occur to a
small extent, typically 10–30% loss of API
• by assay when compared with non-degraded API. This
target is chosen so that some degradation occurs, but
not enough to generate secondary products.
• For this reason the conditions and duration may need to
be varied when the API is especially susceptible to a
particular stress factor.
• In the total absence of degradation products after 10
days the API is considered stable under the particular
stress condition.
5
6. API- 2.3.S.7.1 (a): Summary of stress
testing
6
Stress
conditions
Treatment Results
Heat
Humidity
Oxidation
Photolysis
Acid
Base
Other
7. FPP- Section 2.3.P.8.1(a):
Stress testing
• Formal stress testing for the FPP is not required, except:
Light stressing should be shown for the FPP (ICH
Q1B)
If the API was not demonstrated to be light stable,
and
If the packaging has not been demonstrated to be
light protective
Stress testing is required as part of method validation,
to show the assay and/or related compounds method
is stability-indicating.
7
8. Generic Guideline
“The quality guideline (TRS 970 Annex 4,
Section P.8.1) states, “If “protect from light” is
stated in one of the officially recognized
pharmacopoeias for the API or FPP, it is
sufficient to state “protect from light” on
labelling, in lieu of photostability studies when
the container-closure system is shown to
be light protective.”
8
9. Light stress testing or
photo-protective packaging
We can look at:
“Protect from light” warnings in monographs
“Protect from light” in APIMF
Photo stress testing
Packaging
9
10. FPP
• photostability testing should be conducted on at least
one primary batch of the FPP if appropriate.
• If “protect from light” is stated in one of the officially
recognized pharmacopoeias for the API or FPP it is
sufficient to state “protect from light” on labelling, in lieu
of photostability studies, when the container-closure
system is shown to be light protective.
10
11. Light stressing/Light transmission
What is needed:
Note that photostability testing according to ICH Q1B is
“required”, however we use a pragmatic approach.
a) Either photostability demonstration (progression of API,
FPP exposed, FPP in package) or
b) light transmission data.
photostability testing should be conducted on at least one
primary batch of the FPP if appropriate.
11
12. Conclusion: Light stressing
• Product should be shown to be light stable by
photostability studies
a) showing the dosage form or dosage form in
packaging is photostable.
b) By light transmission studies showing adequate
protection of the packaging.
c) for blisters, which are not light protective, store blisters
in carton (must be clear in QIS and on labels)
• If product is not light stable; label should state that
protect from light and container should be light protective
– light transmission tests should be carried out on the
container closure system
12
13. Storage Conditions
Climatic Zones
• Zone I: 21ºC/45% RH
• Zone II: 25ºC/60% RH (subtropical)
• Zone III: 30ºC/35% RH(hot/ dry)
• Zone IVA: 30ºC/65% RH (hot/ humid)
• Zone IVB: 30ºC/75% RH (hot/very humid)
Long term stability studies should cover all climatic zones if
possible
13
14. 3.2.S.7.1(b)/ 3.2.P.8.1(b):
Accelerated and Long term testing
• Stability data must demonstrate stability of the medicinal
product throughout its intended shelf-life under the
climatic conditions prevalent in the target countries.
• Effective as of September 2011, the required long-term
storage conditions for the WHO Prequalification of
Medicines Programme are 30ºC ± 2º C/75% ± 5% RH.
The use of alternative long-term conditions should be
justified and should be supported with appropriate
evidence.
14
15. When the API or FPP stability studies
were not conducted at PQ conditions:
• The required long-term stability condition within the WHO
Prequalification programme is 30ºC/75%RH for both API
and FPP (Note: 30±2°C/ 65±5% RH is also
acceptable for API), unless documented evidence can be
provided that storage under these conditions is not
possible due to the inherent chemical instability of the
API. In light of this, please provide long-term stability
data for your API at 30C/75%RH or provide documented
evidence that such storage conditions are inappropriate.
15
16. When the API or FPP stability studies
were not conducted at PQ conditions:
API
• If long-term stability data at 30±2°C/ 65±5% RH or
30ºC/75%RH is not available for API, please commit to
generating such data on the next three production scale
batches of XXXXXXXX; provide a signed detailed
protocol describing this stability programme; and commit
to providing an amendment to alter the recommended
storage conditions and retest period once 24 months
stability data has been generated.
16
17. FPP
• In cases where the delay in accepting the dossier in
order to obtain the stability data at 30ºC/75%RH is
unacceptable:
• The required long-term stability condition within the WHO
Prequalification programme is 30ºC/75%RH, unless
documented evidence can be provided that storage
under these conditions is not possible due to the inherent
instability of the product. In light of this, please provide
long-term stability data for your product at 30C/75%RH
or provide documented evidence that such storage
conditions are inappropriate.
17
18. FPP
• If long-term stability data at 30ºC/75%RH is not
available, you are required to commit to initiating studies
at 30ºC/75%RH on the required number of primary
batches; provide a signed detailed protocol describing
the stability programme including a commitment for the
date of initiation of studies, no more than 60 days from
today’s date.
18
19. Storage directions - temperature
• Sometimes the applicant wants “store below 25°C”
when they have demonstrated stability at 30°C.
• Example comment to applicant: As of September 2011
we require stability data at 30C, and when this is
demonstrated “store below 30C” is encouraged on
labelling. Additionally, you should be aware that
procurement agencies prefer products labeled, “store
below 30C” as it indicates that stability was
demonstrated at 30C. You are requested to reconsider
the decision to label the product, “store below 25C”.
We suggest and can explain, we cannot insist.
19
20. 3.2.S.7.1(b)/ 3.2.P.8.1(b):
Accelerated and Long term testing
Condition Storage
temperature (ºC)
Relative humidity
(%)
Minimum time
period
(months)
Accelerated 40 ± 2 75 ± 5 6
Long-term 30 ± 2 75 ± 5
(for both API and
FPP)
65 ± 5
(for API)
6
20
21. Exceptions: Reproductive Health and
2nd line TB drugs 1
• the requirement for stability at the time of submission
only, may be reduced to;
1) no less than 3 months accelerated,
2) plus 3 months long-term data,
for not less than two primary batches of at least pilot
scale or in the case of an uncomplicated1 FPP (e.g.
immediate-release solid FPPs (with noted exceptions),
non-sterile solutions), not less than one batch of at least
pilot scale and a second batch which may be smaller
(e.g. for solid oral dosage forms, 25 000 or 50 000
tablets or capsules) of each proposed strength of the
FPP.
21
22. Exceptions: Reproductive Health and
2nd line TB drugs 2
• One of the primary batches (also called exhibit, pre-
approval, registration, submission, or test batches)
should be the batch that was used for bioequivalence
studies.
• All prequalification requirements for final acceptability of
the dossier remain in effect, without exception;
1) the submission of updated stability data during the
assessment period as it becomes available, and
2) a commitment to provide:
a) stability data on three production batches, and
b) process validation of three consecutive production
batches, to be completed prior to marketing.
22
23. 3.2.S.7.1(b)/ 3.2.P.8.1(b):
Accelerated and Long term testing
• Other storage conditions are outlined in the WHO
stability guidelines:
for FPPs packaged in impermeable and semi-
permeable containers and
those intended for storage in a refrigerator and in a
freezer.
FPPs intended for storage below −20°C should be
treated on a case-by-case basis.
Weight loss from plastic containers should be
reported over the shelf-life (Liquids only).
23
24. Stability of aqueous liquids
Aqueous Liquids in semi-permeable containers – ICH Q1
and TRS953: long term studies should be at 25°C/40%RH
or (for PQ) 30°C/35%RH plus 40°C/25%RH
•Q1A: “Aqueous-based products packaged in semi-
permeable containers should be evaluated for potential
water loss in addition to physical, chemical, biological, and
microbiological stability…Ultimately, it should be
demonstrated that aqueous-based drug products stored in
semi-permeable containers can withstand low relative
humidity environments. ”
25. Container closure systems 1
Semi-permeable (ICH and TRS 953):
•Containers that allow the passage of solvent, usually
water, while preventing solute loss […]
•Examples of semi-permeable containers include plastic
bags and semi-rigid, low-density polyethylene (LDPE)
pouches for large volume parenterals (LVPs), and LDPE
ampoules, bottles, and vials.
•HDPE bottles are considered semi-permeable for storing
liquids.
26. Container closure systems 2
Impermeable
•Containers that provide a permanent barrier to the
passage of gases or solvents, e.g. sealed aluminium
tubes for semisolids, sealed glass ampoules for solutions
(ICH/TRS 953) and (TRS 953 only) aluminium/aluminium
blisters for solid dosage forms. (Be careful of Al/Al, it
depends on the sealing.)
27. Container closure systems 3
• TRS 953: “Sensitivity to moisture or potential for solvent
loss is not a concern for FPPs (for liquids) packaged in
impermeable containers that provide a permanent barrier
to passage of moisture or solvent. Thus stability studies
for products stored in impermeable containers can be
conducted under any controlled or ambient relative
humidity condition.
• Note: This does not apply to AL/ Al blisters. For Al-Al
blisters, humidity in stability studies is just as important
as for bottles. It is just that moisture permeability does
not have to be tested for the package.
27
29. Section 3.2.S.7.2/ 3.2.P.8.2:
Post-approval stability protocol
• number of batch(es) and different batch sizes, if
applicable;
• relevant physical, chemical, microbiological and
biological test methods;
• acceptance criteria;
• reference to test methods;
• description of the container-closure system(s);
• testing frequency;
• description of the conditions of storage
29
30. Information on stability studies
• – storage conditions;
• – strength;
• – batch number, including the API batch number(s) and
• manufacturer(s);
• – batch size;
• – completed (and proposed) test intervals.
• – container-closure system including orientation (e.g.
erect, inverted, on-side) where applicable; important for
liquids and semi-solids (e.g. erect, inverted, on-side):
This is to study the possible interaction of the container
closure system (the container and the closure) with the
product.
30
31. Section 3.2.S.7.3/ 3.2.P.8.3:
Stability data
• Results of the stability studies should be presented in an
appropriate format :
tabular,
graphical,
Narrative
• Summary of analytical methods
Information on the analytical procedures used to
generate the data and validation of these procedures
should be included.
31
32. Stability reports
• General information: name, manufacturing sites, date of
manufacturing; batch number, batch size.
• Container closure system, tests and acceptance criteria ,
test frequency, storage conditions—should in line with
the protocol
• Evaluation of stability data-- any significant change? Out
of specification? out of trend?
• Conclusions
– retest period for drug substance, or shelf life, if
applicable
– storage condition
32
33. API: Retest period
• A retest period should be derived from the stability
information and should be displayed on the container label.
• After this retest period a batch of API destined for use in the
manufacture of an FPP could be retested and then, if in
compliance with the specification, could be used immediately
(e.g. within 30 days). If retested and found compliant, the
batch does not receive an additional period corresponding to
the time established for the retest period. However, an API
batch can be retested multiple times and a different portion of
the batch used after each retest, as long as it continues to
comply with the specification. For APIs known to be labile
(e.g. certain antibiotics) it is more appropriate to establish a
shelf-life than a retest period.
33
35. Stability issue – specifications have
changed
• Often during assessment specs are revised (by request
usually) but there is no attention paid to whether stability
data supports the change.
• [This is another reason why it is so important to compare
previous specs to the revised version provided.]
• It is not sufficient to accept only a commitment for
results for the new specification.
• When we accept a shelf-life we are saying we are
satisfied that the specifications will be met based on
data we have assessed.
36. Stability issue – specifications have
changed
If the revised limits can be assessed using current
data, just ensure the new limits are met by most recent
stability data.
•Example tightened impurity limits: we can usually tell
whether the new limits have been met by reviewing the
available data
Imp A: up to 0.2% reported; meets new limit of NMT 0.1%
Exception in this case is TLC: semi-quantitative results
were provided:
Imp A: < 0.2% reported; can’t tell if new limit (0.1%) is met
37. Stability issue – specifications have
changed
The revised limits may require new testing/reporting,
such as inclusion of a limit for a new impurity or a different
dissolution timepoint. In these cases, the available data is
insufficient:
1. If studies are completed: Request available data on
retained samples if not far beyond expiry, or available new
studies
2. If studies are ongoing: Request that data at subsequent
stations include the revised limits.
38. Stability-indicating parameters
• Stability-indicating parameters must be understood for
the API and FPP.
• API: any parameter susceptible to change (appearance,
assay, impurities*, others specific to the API e.g.
polymorphism if necessary)
• Why all specified impurities, and not just degradation
products for the API? The way to determine if an impurity
is also a degradant is to do the stability and monitor
known impurities. A process impurity could also turn out
to be a degradant. The degradants for an API by one
manufacturing process may differ from that of another,
for example due to the presence of trace metals or other
reagents.
39. Stability-indicating parameters
FPP:
Physical (description, moisture, quality parameters (DT,
dissolution));
• Moisture is particularly important for solid orals in blisters
and strips, and moisture-sensitive products in bottles.
Chemical (assay, degradants, preservatives);
Efficacy of additives
Container/closure interactions, when applicable (e.g.
liquid in plastic);
40. Evaluation and Extrapolation of
results
• if significant change was not observed within 6 months at
accelerated condition and the data show little or no
variability, the proposed shelf-life could be up to twice
the period covered by the long-term data, but should not
exceed the long-term data by more than 12 months
• The proposed storage statement and shelf-life (and in-
use storage conditions and in-use period, if applicable)
for the FPP should be provided. The recommended
labelling statements for use based on the stability
studies, are provided in the WHO stability guidelines
40
41. Provisional shelf-lives 1
• Ideally, these would not exist. As long as there are
significant question(s) and the data did not cover the
proposed shelf-life, updated data should be
requested/provided.
• Example problem: 12 mo data provided in blisters and
then the study was discontinued. A provisional 24 mo
shelf-life was accepted. Is this okay?
• No. You can’t extrapolate based on data for batches
when the study on these batches will not be continued
over the extrapolated period.
42. Provisional shelf-lives 2
Never accept extrapolation for cancelled studies. ICH
Q1E:
“a retest period or shelf life granted on the basis of
extrapolation should always be verified by additional long-
term stability data as soon as these data become
available.”
WHY? 1) we don’t know why the studies were cancelled.
2) we don’t have the normal assurance of the “primary
stability commitment”, and 3) if they cancelled studies (in
the above case they claim because of low market
potential), the odds of them starting a new study are slim.
This is very risky and against all practices.
43. Updated stability data and
extrapolation – what NOT to say
“Please provide update stability data. In order to support of
24 months shelf life of the product, long term stability data
up to at least 12 months should be provided, with
commitment to continue long term testing for a period of
time sufficient to cover the whole proposed shelf life.”
The above suggests that we will accept 12 months data,
and extrapolate on this, even if longer data is available.
What TO say:
“In order to support the proposed shelf-life, you are
requested to provide available updated stability data.”
44. Extrapolation
1. Ask for the available updated stability data each time
comments are going out.
2. Don’t imply that extrapolation is a guarantee as in the
example question. It depends on the actual data
provided.
3. Don’t offer extrapolation unless it has specifically been
proposed by the applicant.
45. 2.3.S.7.1(b)/ 2.3.P.8.1(b):
Summary of accelerated and long
term testing
• Summary of stability results observed
45
Storage
conditions
(ºC, % RH)
Strength and
Batch number
Batch
size
Container
closure
system
Completed (and
proposed) test
intervals
Test Results
Description
Moisture
Impurities
Assay
46. Other stability studies
Hold time studies: validate holding times - how long an
intermediate can be stored, including bulk product prior to
final packaging
In-use studies: studies to show that normal in-use of the
product will not result in significant changes in the product
Transport studies: studies to show a bulk product will still
meet the release limits after transportation to the packaging
site
Each of these studies have their own requirements.
46
47. Hold time Studies 1
Summary of acceptable hold times
A maximum processing time of one month (30 days) is
acceptable without validation. (industry standard)
Any hold time for an intermediate or the bulk product >30 days
must be supported by stability studies.
In addition, cumulative hold times should not exceed 90 days, or
additional supporting data is required.
47
48. Hold time studies 2
These are a type of stability study to determine hold times
for example for blend, cores and final coated tablets in bulk.
Necessary when hold time > 30 days or there are multiple
hold times (e.g. 30+30+30+30).
•All stability-indicating parameters should be included in the
studies.
•The applied limits are important. Release limits should be
applied to final tablets, not just shelf-life.
48
49. Hold time studies 3
Beware of even short hold times for liquid intermediates.
Example comment:
• The API-loaded suspension is allowed to be stored for
three days before being further used for processing. The
suspension contains HPMC and lactose, both of which
could promote microbial growth. Please provide the
supporting data for microbial stability of the
suspension and the chemical stability of the API for
the proposed waiting period of three days during
processing.
49
50. Hold time studies 4
Common issue: a number of intermediates have hold
times
Beware of cumulative hold times, even if separately
validated
The date of production of a batch is defined as the date that
the first step is performed involving combining the API with
other excipients.
Even if appropriate hold studies have been provided to
support hold times, the hold times still may be
unacceptable.
50
51. Hold time studies 5
Recent example (controlled release (CR) tablet):
Blend 25 days
Compressed tablets 30 days
Seal coated tablets 5 days
CR coated tablets 30 days
Laser drilled tablets 30 days
Bulk tablets 1 months
Total hold time > 5 months before packaging! Shelf-life is
only 24 months. This should be questioned! E.g. Flag
this if >3 months total
51
52. Hold time studies 6
Comment out:
You have indicated cumulative hold times prior to the
stage of packaging of the product that add to over 5
months. You are reminded that the start of shelf-life is
defined as the time of first mixing of an excipient with the
API. You are requested to significantly reduce the
hold times so that the maximum processing time will
be kept at a reasonable duration (e.g. 30 days) or
provide additional evidence that a product subject to
the cumulative effect of the largest hold times would
still meet release specifications as well as shelf-life
specifications over the remaining shelf-life.
52
53. In-use studies 1
TRS 970 Annex 4 states: Any in-use period and
associated storage conditions should be justified with
experimental data, for example, after opening,
reconstitution and/or dilution of any sterile and/or multidose
products or after first opening of FPPs packed in bulk
multidose containers (e.g. bottles of 1000s*). If applicable,
the in-use period and storage conditions should be stated
in the product information.
*only for rifampicin containing products and highly
hygroscopic products.
In use period of 28 days generally accepted without
data (most products).
53
54. In-use studies 2
Standard comment out:
It is noted that a two month in-use period is claimed for the
product. As outlined in the quality guideline (TRS 970
Annex 4, P.8.1 p. 184), any in-use period and associated
storage conditions should be justified with experimental
data. A minimum of two batches of at least pilot scale*
should be subjected to the test. At least one of the
batches should be chosen towards the end of its shelf-
life.
* May use lesser requirement for uncomplicated FPPs
54
55. In-use studies 3
As far as possible the test should be designed to simulate
the use of the product in practice (i.e. the same bottle
opened at each interval), taking into consideration the
filling volume of the container. At intervals comparable to
those that occur in practice, appropriate quantities should
be removed by the withdrawal methods normally used and
described in the product literature.
In the case where the package size is inadequate for the
full study: One unit (tablet or capsule) may be withdrawn
and then replaced.
55
56. In-use studies 4
• Rather than just opening the bottle, the protocol should
specify that at least one capsule is picked out each time
it is opened, and then it may be immediately returned to
the bottle for future analysis. This is to ensure that air
moves in the bottle as it is expected to during normal
use.
56
57. Transport studies 1
It is transportation of bulk product that requires transport
studies. Transportation of packaged product is not
normally required (may be requested in special cases).
If there are stability issues with the FPP, then study results
may be requested.
57
58. Transport studies 2
If there are no stability issues with the FPP, we do not
pursue study results. Instead a protocol is sufficient,
including:
at least one batch of at least pilot scale;
confirmation of whether the product will be shipped in a
controlled environment, with or without transportation
logging devices; and
If not a controlled environment, assessment of
environmental conditions to which the product will be
exposed during transportation, and studies to support the
stability of the product in the bulk package at the extremes
of the likely conditions.
58
60. Assessment Tips for stability 1
1. Has the applicant provided the stability protocol? Check
the conditions used in the stability studies
2. Has the applicant submitted accelerated stability
studies? 40±2°C/ 75±5% RH.
3. Has the applicant submitted long term stability studies?
30±2°C/ 75±5% RH for API and FPP (30±2°C/
65±5% RH is also acceptable for API) except for
justified cases.
60
61. Assessment Tips for stability 2
4. Check the period of the stability studies submitted:
atleast 6 months for both accelerated stability studies
and long term stability studies. Exceptions: RH products
and 2nd line TB drugs
5. Check the number of batches used in the stability
studies
6. Check the batch size of the batches used in the stability
studies. Are they acceptable: atleast 2 batches of pilot
scale or for an uncomplicated FPP, one of pilot scale
and second batch which may be smaller
61
62. Assessment Tips for stability 3
7. Check the type of the container closure system
including the type of the material of the cap used in the
stability studies: What is the type of packaging type
used including the type of cap, if applicable? Is it the
same as that declared in section 2.3.P.7?
8. Check the conditions used in the stability studies
9. Check the period of the stability studies submitted:
atleast 6 months for both accelerated stability studies
and long term stability studies. Exceptions: RH products
and 2nd line TB drugs
62
63. Assessment Tips for stability 4
10.Are all the stability indicating tests included?
11.Check the shelf life specifications against the
specifications used in the stability studies.
12.Check the results for each parameter at each test
station to confirm whether the results are all within the
limits (specifications). No failured
13.Is there any significant change observed in the stability
study results?
14.Summarize the trends for each parameter.
63
64. Assessment Tips for stability 5
15.Is there mass balance in the stability study results?
16.Do the stability studies submitted support the proposed
shelf life?
17.Do the stability studies support the proposed storage
condition? Does the compendia state any special
storage condition for the product?
The storage condition should include the provisions
stated in the compendia. The container closure system
should provide the necessary protection.
64
65. Assessment Tips for stability 6
Stability Commitments
18.Has the applicant submitted written and signed stability
study commitments (primary stability study commitment,
commitment stability study commitments and ongoing
stability study commitments)?
19.Check the batches stated under the primary stability
commitment: primary batches
20.Check the batches stated under the commitment
stability studies: first three consecutive commercial
batches.
21.Check the batches stated under the ongoing stability
study commitment: atleast one batch per year
65
66. References
• TRS_970- Annex 4 Generic Guideline
• QA Talks by L. Paleshnuik, Lead Quality Assessor PQP.
• Presentation- EAC Joint Session July 2013: Assessment
part XIV section P.8, L. Paleshnuik, Lead Quality
Assessor PQP.
• Presentation- EAC Joint Session July 2013: Process of
Assessment – API areas S.5, S.6, S.7, Hua Yin
• ICH Q1A, Q1B, Q1D, Q1E, Q2,
• WHO Technical Report Series, No. 953, Annex 2
66
A maximum processing time of one month (30 days) is acceptable without validation. (industry standard)
------ Maximum processing from dispensing to the final coating
Any hold time for an intermediate or the bulk product >30 days must be supported by stability studies.
In addition, cumulative hold times should not exceed 90 days, or additional supporting data is required.
------- Example from previous QA talk: 16.5 months for a CR tablet (shelf-life 24 months)
Blend 45 days
Compressed tablets 90 days
Seal coated tablets 7 days
CR coated tablets 90 days
Laser drilled tablets 90 days
Bulk tablets 6 months