1. The transition of product from ideality to non ideality
STABILTY STUDIES
The transition of product from ideality to non ideality
after manufacture
Dr. Akhilesh Gupta

2. Applicability of stability study
STABILTY STUDIES
Purpose of stability testing:
The aim of stability study is to support minimum release potency or maximum shelf life that will assure that the product maintains a minimally effective potency throughout its shelf life and in some cases, to assure that degradation products do not exceeds levels shown to be safe in clinical or preclinical studies
Applicability of stability study
Stress testing and interpretation of data to establish Shelf life and expiry date determination
Stability studies required for various regulatory submission of NDA/ANDA-MHRA/USFDA.
Regulatory requirements of Schedule-M?
Stability studies upto R&D / Pilot scale – Requirements / conditions and importance of such studies for further commercialization stages.

3. Terminologies used in stability
Accelerated Testing: studies are designed to increase the rate of chemical degradation or physical change of drug product by using exaggerated storage conditions as a part of formal stability study
Bracketing: the design of stability schedule such that only samples on the extremes of certain design factors such as strength, pack size are tested at all time points as in a full design
Climatic Zone :
Expiration date: placed on container label designating the tim prior to which a batch p product is expected to remain within approved shelf lif specifications
Intermediate testing: a minimum of four points(e.g. 0,6,9,12 months)
Long term testing: under recommended storage conditions.
Matrixing:
Shelf life:
Stress testing : to assess the effect of the sever conditions such studies include

4. STABILITY STUDIES Typical Stress condition in pre-formulation stability studies
Sr. No.
Stress factor
Conditions
Concentration of API
Time 1
Heat
60 0C
1:1 with diluent
1-10 days 2
Humidity
75% Relative Humidity or grater
Solid State 3
Acid
0.1N HCl
2:1 4
Base
0.1N NaOH 5
Oxidation
3% H2O2
1:1
1-3 days 6
Photolysis
Metal halide, mercury, xenon or UltraViolt-B fluorescent lamp 7
Metal ions
0.5M Fe2+,or Cu2+
1:1 with solution of metal ions

5. 2009 WHO guidelines for Stability Testing
STABILTY STUDIES
2009 WHO guidelines for Stability Testing
WHO Technical Report Series, No. 953,2009
Annex 2
Stability testing of active pharmaceutical ingredients and finished pharmaceutical products
1. Introduction
1.1 Objectives of these guidelines
1.2 Scope of these guidelines
1.3 General principles
2. Guidelines
2.1 Active pharmaceutical ingredients
2.2 Finished pharmaceutical products

6. 2.1 Active pharmaceutical ingredients 2.1.1 General
STABILTY STUDIES
2.1 Active pharmaceutical ingredients
General
2.1.2 Stress testing
Selection of Batches
Container Closer System
Specification
Testing frequency
Storage Conditions
Stability commitment
Evaluation
Statements and Labeling
Ongoing Stability studies

7. 2.2 Finished Pharmaceutical product
STABILTY STUDIES
2.2 Finished Pharmaceutical product
General
Selection of Batches
Container Closer System
Specification
Testing frequency
Storage Conditions
Stability commitment
Evaluation
Statements and Labeling
In Use stability
Variations
Ongoing Stability studies
3. Glossary
References
Appendix 1
Long term stability testing conditions as identified by WHO member states

8. WHO STABILTY STUDIES 1.2 Scope of these guidelines
These guidelines are apply to new and existing APIs and addresses information to be submitted in original and subsequent applications for marketing authorization of their related FPPs for human use. These guidelines are to applicable for stability testing for biological
1.3 General principles
The purpose of stability testing is to provide evidence o how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature RH and light. The stability program also includes the study of product related factors that influence the quality, or example interaction of API with excipients, container closer system and packing material . In fixed dose combinations FPPs (FDCs) the interaction between two or more APIs also has to be considered.
As a result of stability testing a retest period for the API ( in experimental cases e.g. for unstable APIs, a shelf life is given or shelf life for FPPs an be established and storage conditions can be recommended
Various analysis have been done to identify suitable testing conditions for WHO member states based on climatic data and are published in the literature (6-9) on the basis of each member can make its decision on long term (real tome) stability testing conditions,. These member states that have noticed WHO of the long term stability testing conditions they requires when requesting a marketing authorization are listed in Appendix I

9. ICH Quality topics
Q1 A-F Stability
Q2 A-B Analytical validation
Q3 A-C Impurities
Q4 A-B Pharmacopoeias
Q5 A-F Biotechnological Products
Q6 A-B Specifications
Q7 A Good manufacturing practice
Q8-10 Pharmaceutical development, Risk management and quality system

10. ICH STABILTY STUDIES 1.2 Scope of the Guideline
The guideline addresses the information to b submitted in registration application for ne molecules entities and
associated drug products. This guideline does not currently seek to cover the information to be submitted for
abbreviated or abridged applications, variations, clinical trial applications etc.
Specific details of the sampling and testing for particular dosages form in their proposed containers are not
covered in this guideline.
Further guidance on new dosages forms an biotechnological/biological products can b found in ICH guidelines
Q1C and Q5C respectively.
1.3 General principles
The purpose of stability testing is to provide evidence on how the quality of a drug substances for drug products
varies with time under the influence of a variety of environmental factors such as temperature humidity and
light to establish a retest period for a for the drug substances or shelf life for drug products and recommended
storage conditions
The choice of the test conditions defined in the guideline is based on an analysis of the effects of climatic
conditions in the three regions of the EC, Japan and the United states. The mean kinetic temperature in
any part of the world can be derived from climatic data , and the world can be divided into our zones, I-IV.
This guideline addresses climatic zones I and II. The principle has been established that stability information
generated in any one of three regions of the EC, Japan and United States would be mutually acceptable to the
other two regions . Provided the information is consistent with this guideline and labeling is an accord with
national requirements.

11. ICH Quality topics -Update
Code
Subject
Update
Q1 A-F
Stability
No Change in status after 2006 (withdrawal of Q1 F)
Q2 A-B
Analytical validation
No Change since incorporation of addendum in core guideline in 2005
Q3 A-C
Impurities
No change after 2003 in Q3 A and B, progress in Q3C, Latest March 2010
Q4 A-B
Pharmacopoeias
Progressed with addition of annexure till as late as June 2010
Q5 A-F
Biotechnological Products
No Change in status of original documents (2005)
Q6 A-B
Specifications
No Change in status of original documents (1999)
Q7 A
Good manufacturing practice
No Change in status of original documents (2000)
Q8-10 (Q & A)
Pharmaceutical development, Risk management and quality system
Progressed with issue of Q and A document in Oct 2009

12. STABILTY STUDIES Conceptual differences in WHO guideline from ICH
API:
Active pharmaceutical ingredient
FPP:
Finished Pharmaceutical product 2.
Guidelines
2.1
Change
Yes/No
2.2
2.1.1
General No
2.2.1
2.1.2
Stress testing
Yes
2.2.2
Selection of Batches
2.1.3
2.2.3
Container Closer System
2.1.4
2.2.4
Specification
2.1.5
2.2.5
Testing frequency
2.1.6
2.2.6
Storage Conditions
2.1.7
2.2.7
Stability commitment
2.1.8
2.2.8
Evaluation
2.1.9
2.2.9
Statements and Labeling
2.1.10
2.2.10
In Use stability
2.1.11
Ongoing Stability studies
N/A
2.2.11
Variations
2.2.12

13. Stress Testing: ICH/WHO Definition
STABILTY STUDIES
Stress Testing: ICH/WHO Definition
1. Stress Testing (Drug Substance): Studies undertaken to elucidate the intrinsic stability of the drug substance . Such testing is a part of development strategy and is normally carried out under more severe conditions than those used for accelerated testing.
2. Stress Testing (Drug Product): studies undertaken to access the effect of severe conditions on the drug product, such studies includes photo stability testing and specific testing on certain products (e.g. metered dose, Inhalers, creams, emulsions, refrigerated aqueous liquid products)
WHO- Definition guideline on stability Evaluation of Vaccines.
Stress Testing: Studies performed to determine the impact of extreme environmental factors such as light and extreme temperature. These studies are not usually performed as a part of a stability program but, are used to establish protective pacing and container conditions, and to support exclusionary labeling.

14. STABILTY STUDIES
ICH Harmonised Tripartite Guideline Stability testing of New drug Substances and Products Q1A(R2) Stress Testing: Stress testing of the drug substances can help identify the likely degradation products, which can in turn help to establish the degradation pathways and the intrinsic stability of the molecule and validates the stability indicating power of the analytical procedures used. Evaluation: Any valuation should consider not only the assay but also the degradation products and other appropriate attributes. Evaluation for stability Data Q1E 2.1 General Principles: Adequacy o the mass balance should be assed, factors that can cause an apparent lack of mass balance should be considered, for example, the Mechanism of degradation and the Stability-indicating capability and inherent variability of the analytical procedures.

15. STABILTY STUDIES
Stress Testing Development of Stability-Indicating Method (SIM) Validation of SIM Quantitative estimation of DPs Establishment of mass balance Characterization of mass DPs Degradation pathway an mechanism

16. Drug Degradation Product(s)
STABILITY STUDIES
Drug Degradation Product(s)
Direct Injection LC Separation
MS study Origin of fragments MS Study +
MS/TOF Accurate mass of molecular ion(s) & fragments MS/TOF Analysis
Analysis
Determination o chemical formula for molecular ion, losses
& fragments; ring + double bonds; Nitrogen rule
HD Exchange Number of labile hydrogen's Online H/D Exchange
fragmentation pattern of drug & degradation product(s)
Assignment of structure to degradation product(s) based
on comparison of mass data & fragmentation pattern to the drug
justification through mechanistic explanation to the formation
of degradation product(s) from drug in a specific reaction condition
st stat at

17. STABILITY STUDIES
A Chemist proposes A Pharmaceutical scientist Disposes
Reactants DRUG
Intermediates, Intermediates
DRUG Degradation products
A degradation products may be….
Active
Inactive
Toxic
Genotoxic
So regulatory directive… asks about drug is % in formulation
but tell that is 2-3 %?

18. STABILTY STUDIES
At least three primary batches shall be studied for stability out o which two batches shall be at least pilot scale batches & third on can be small if justified . Stability study can be performed on each individual strength & containers size of the drug product.
Selection of batches (API)
Additional in WHO for existing active substances that are known to be stable, data from at least two primary batches should be provided
Selection of batches (FPP)
In the case of conventional dosage forms with API known to be stale, data fro at least to primary bathes should b provided

19. STABILTY STUDIES
Testing Frequency:
For long term stability:
Testing frequencies for the product with proposed shelf life of at least 12 months, should normally be every three months over first year; every 6 months over the second year, and annually thereafter though the proposed shelf life.
b) For accelerated Stability:
At the accelerated storage conditions, a minimum of three time points, including initial and final points(e.g. 0,3,6 months) ,for 6 months study is recommend.
c) Intermediate stability studies:
A minimum o our points, including the initial & final points (e.g.0,6,9,12 months), from a 2 months study is recommended

20. Storage conditions Revised criteria to classify Climatic Zone and recommended testing conditions
Definition
Mean annual T measured in the open air / partial water vapor pressure
Testing conditions I
Temperature Climate
≤15 /≤11 hPa
210C/45%RH II
Subtropical & Mediterranean
>15 to 22 / >11-18hPa
250C/60%RH
III
Hot & Dry
>22/≤15 hPa
300C/35%RH
IVA
Hot & Low humid
>22/> 15to 27 hPa
300C/60%RH
IVB
Hot & moderately humid
>22 / 27 to 30 hPa
300C/70%RH
IVC
Hot & very humid
>22 />30hPa
300C/75%RH

21. Current criteria to classify Climatic Zone and recommended testing conditions
Definition
Mean annual T measured in the open air / partial water vapor pressure
Testing conditions I
Temperature Climate
≤15 /≤11 hPa
210C/45%RH II
Subtropical & Mediterranean
>15 to 22 / >11-18hPa
250C/60%RH
Hot & Dry
>22/≤15 hPa
300C/35%RH
IVA
Hot & humid
>22/> 15to 27 hPa
300C/60%RH
IVB
Hot & very humid
>22 />30hPa
300C/75%RH

22. Storage Conditions (API and FPP)
Additional in WHO General Case Active pharmaceutical ingredients intended for storage in a refrigerator
Study
Storage condition
Minimum time covered y data at the time of submission
Long term
25 ±2 0C/80%RH±5%RH or
30±2 0C/65%RH±5% RH or
30±2 0C/60%RH±5%RH
12 months or 6 months as described in points 2.1.7
Intermediate
6 months
Accelerated
40±2 0C/60%RH±5%RH
Study
Storage condition
Minimum time covered y data at the time of submission
Long term
5 ±3 0C
12 months
Accelerated
25 ±2 0C/80%RH±5%RH or
30±2 0C/65%RH±5% RH or
30±2 0C/75%RH±5%RH
6 months

23. Evaluation
Evaluation (API)
Additional in WHO
Where the data shows little degradation and so little variability that it is apparent from looking at the data that the requested shelf life will be grated. It is normally unnecessary to go through the statistical analysis. However a provisional shelf life of 24 months may be established provided the following conditions are stratified
The API known to be stable(not easily degradable)
Stability studies as outlined above in setion2.1.11have been performed and no significant change have en observed.
Supporting data indicates that similar formulation have been assigned a shelf life of 24 months or more.
The manufacturer will continue to conduct long term studies until the proposed shelf life has been covered and the results obtained will be submitted to the national medicines regulatory authority

24. Evaluation
Evaluation (FPP) ICH Any evaluation should consider not only the assay but also the degradation products and other appropriate attributes. Where appropriate attention should be paid to reviewing the adequacy of the mass balance and different stability and degradation performance. Different in WHO Any evaluation should consider not only the assay but also the degradation products and other appropriate attributes. Where appropriate attention should be paid to reviewing the adequacy of evaluation linked to FPP stability and degradation behavior during the testing

25. Statements and labeling
Storage conditions FPP Additional in WHO General case
Study
Storage condition
Minimum time covered y data at the time of submission
Long term
25 ±2 0C/60%RH±5%RH or
30±2 0C/65%RH±5% RH or
30±2 0C/75%RH±5%RH
12 months or 6 months as referred in section 2.2.6
Intermediate
30 ±2 0C/60%RH±5%RH
6 months
Accelerated
40 ±2 0C/75%RH±5%RH

26. Labeling statements Recommended labeling statements for active ingredients(APIs)
Testing conditions under which the stability of the API has been demonstrated
Recommended labeling statements
25 0C/60%RH (Long-term)
40 0C/75%RH (Accelerated)
“ Do not store above 25 0C”
30 0C/65%RH (intermediate failure of Accelerated)
30 0C/65%RH (Long-term)
“ Do not store above 30 0C”
30 0C/75%RH (Long-term)
50C ±3 0C
“ store in a refrigerator(20C to 80C)”
-200C ±5 0C
“ Store in freezer”

27. Labeling statements Recommended labeling statements for active ingredients(FPPs)
Testing conditions under which the stability of the API has been demonstrated
Recommended labeling statements
25 0C/60%RH (Long-term)
40 0C/75%RH (Accelerated)
“ Do not store above 25 0C”
30 0C/65%RH (intermediate failure of Accelerated)
30 0C/65%RH (Long-term)
“ Do not store above 30 0C”
30 0C/75%RH (Long-term)
50C ±3 0C
“ store in a refrigerator(20C to 80C)”
-200C ±5 0C
“ Store in freezer”

28. Additional labeling statements for use where results of the stability indicating demonstrates limiting factors
Limiting factor
Additional labeling statements where relevant
FPPs that can not tolerate refrigeration
“Do not refrigerate or freeze”
FPPs that can not tolerate freezing
“Do not freeze”
Light sensitive FPPs
“protect from light”
FPPs that can not tolerate excessive heat
“Store and transport not above 30 0C “
Hygroscopic FPPs
“store in a dry condition”

29. STABILTY STUDIES
Appendix 1 Long term stability testing conditions as identified by WHO member states In order to be able to reduce the amount of stability testing required, the number of different long-term testing conditions must be reduced to a sufficient extent. This approach was proposed by Paul Schumacher in 1973(1) and by Wolfgang Grimm in 1986(2), and in 1998(3) when they defined four different long-term testing conditions, which match with the climatic conditions of the target markets categorized in just four different climatic zones. This concept is described in regulatory guidelines and pharmacopeias and has become an established standard in developing finished pharmaceutical products(FPPs). At the fortieth meeting of the WHO expert committee on specifications for pharmaceutical preparations held in Geneva in October 2005(4) it was recommended to split the current climatic zone IV (hot and humid) into two zones: climatic zone IVA for which 30/65% RH will remain the standard long-term testing condition and climatic zone IVA for which if justified, 30/75%RH will the long-term testing conditions.

30. STABILTY STUDIES
Protocol
Type, size and number of batches
Containers and their storage orientations
Test parameters
Test methods
Acceptable criteria
Sampling time points
Test storage conditions
Durations of studies at the time of submission

31. STABILITY STUDIES
Determination of expiry date from long term data
Accelerated data considered only supportive
Shelf-life Calculations from long term data
Graphically evaluate the data whether data from different bathes is poolable or not. Statically evaluate through analysis of variance (ANCOVA), p>0.25
Evaluate whether mathematical transformation of data needed, based on test for goodness of fit
Calculate expiry date based on 95% one sided confidence limits
Assessment of batch to batch similarity
Data pooling suggested for different batches, only if data is statically proven to be homogeneous
Different tests applied: Test for zero slope- To detect no change in data with time
Test or equality of slopes of regressions
Test for equality of intercepts

32. STABILITY STUDIES
Expiry date calculation based on 95 % confidence limit Equation for 95 % lower confidence limits C= Co + ko .t-Ts√(1+n)/n + [(t-t’)2/∑(t-t’)2] Where t’= average of time periods Co= intercept of the regression line Ko = Sloe of the regression line T= students t value for n-2 degrees of freedom n= number of stability points, ti t= is the average of ti values S2= sum of the squares of distances of the actual stability points from the regressed line

33. STABILTY STUDIES
Maximum shelf life or retest period allowed Long term and accelerated data shows little or no change over time and little or no variability or amenable to statistical analysis and analysis performed: Y= up to 2X but not exceeding X+12, where X is the period for which data submitted

34. STABILITY STUDIES Evaluation of stability data to establish Shelf Life-for drug products If accelerated Satiability data for 6 month is OK
x y
Accelerated Long term y = 2 x
(6 months) (9 months OK) Shelf life/ re-test date is 18 month
Accelerated Long term y = 2 x or x + 12
(6 months) (12 months OK) Shelf life/ re-test date is 24 month
Accelerated Long term y = x + 12
(6 months) (12 months not OK) Shelf life/ re-test date is 24 month
Statistical support possible
Accelerated Long term y = upto 1.5x, but more than x + 6
Statistical support also not possible
(6 months) (18 months OK) Shelf life/ re-test date is 30 month
(6 months) (24 months OK) Shelf life/ re-test date is 36 month
Accelerated Long term y = x
(6 months) (36 months OK) Shelf life/ re-test date is 36 month,
No extrapolation beyond 36 month

35. Evaluation of stability data to establish Shelf Life-for drug products
STABILITY STUDIES
Evaluation of stability data to establish
Shelf Life-for drug products
If accelerated Satiability data for 6 month is NOT OK
x y
Accelerated intermediate & Long term y = 2 x
(6 months) (12 months OK) Shelf life/ re-test date is 18 months
Accelerated intermediate OK & Long term y = x + 3
(6 months) Statistical data not supportive
Accelerated No extrapolation shorter
(6 months) retest period shelf life

36. STABILITY STUDIES
Retest period: The period of time during which the drug substance is expected to remain within its specification and therefore, can be used in the manufacture of a given drug product, provided that the drug substances has been stored under the defined conditions. After this period, a bath o a drug substance destined for use in the manufacturer of a drug product should be retested or compliance with the specification and then used immediately. A bath of drug substance 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

37. Stability studies required for various regulatory submissions an other important aspects: Regulatory Guidelines ICH stability testing guidelines
ICH Code
Guidance Title
Remarks
Date of Finalization
Q1A
Stability testing of new drug substances & products (second revision)
The guidance provides recommendations on stability testing protocols including temperature humidity & trial ration
6-feb-2003
Q1B
Stability testing : photo stability testing of new drug substances & products
This forms an annex to the main stability guidance & gives guidance to the basic testing protocol required to evaluate the light sensitivity & stability o new drugs & products
5-nov-1996
Q1C
Stability testing for new dosage forms
It extends the main stability guidance on new formulation of already approved medicines and defines he circumstances under which reduced stability date can be accepted
5 Nov 1996
Q1D
Bracketing and matrixing designs for stability testing of drug substances and products
Describes general principal for reduced stability testing and provides example of Bracketing and matrixing designs
5 Feb 2002
Q1E
Evaluation of stability date
Extends the main guideline by explaining possible situation where extrapolation of retest period / Shelf life beyond the real time data may be appropriate. Further more it provides example of statistical approaches to stability date analysis
5 Feb 2003
Q1F
Stability ate package for registration applications in climatic zones III and IV
Provides guidelines on specific stability testing requirements for climatic zone III and IV. Besides proposing acceptable storage conditions for long term and accelerated studies. It gives guideline on data to cover situations of elevated temperature and / extreme of humidity
(Withdrawn)
Q1G
Stability testing of Biotechnological /biological products
describes generation an submission of stability data of well characterized proteins an peptides, their derivatives an products of which they are components
30 Nov 1995

38. Stability studies required for various regulatory submissions an other important aspects: Regulatory Guidelines Currently listed stability tests guidelines issued by EMEA, Europe
Reference Number
Name of the guideline
Effective date
EMEA/HMPC/3626/09
Reflection paper on stability testing of herbal medicinal products and traditional herbal medicinal products
Release for consultation in January 2009 deadline for consultation 15th may 2009
CPMP/QWP/576/96Rev.1
stability testing for applications for variation to a marketing authorization
Dec 2005, Concept paper CPMP/CHMP/CVMP/QWP/63033/2010 issued on march 2010 to revise the guideline end of consultation 30Apr 2010
CPMP/QWP/122/02Rev.1corr
Stability testing of existing active ingredients and related finished products
March 2004, but on march 2007 minor correction was done to revision 1 the wording in paragraph was revised to clarify the need for testing under accelerated intermediate storage conditions
CPMP/QWP/609/96Rev.2
Declaration of storage condition for medicinal products particulars and active substances
Oct 2003 minor revision in Sep 2007, only to improve the clarity of the text
EMEA/CVMP/422/99/Rev.3
Guidelines of declaration of storage condition : a) in the product information of pharmaceutical veterinary medicinal products b) for active substances
Oct 2003 minor revision in Nov 2007, only to improve the clarity of the text
CPMP/QWP/072/98
Annex: start of the shelf life of the finished dosages forms
Dec 2001
CPMP/QWP/2034/99
In-use stability testing of human medicinal products
Sep 2001

39. Stability studies required for various regulatory submissions an other important aspects: Regulatory Guidelines Regional and national guidelines on stability testing
Region
Title
Updates
Arab states (cooperation council for the Arab states of the Gulf)
The GCC Guidelines for stability testing of
drug substances and pharmaceutical products
Edition Two 1428H-2007G
ASEAN
ASEAN guidelines on stability study
of drug products
22 Feb 2005
Brazil
Guide or stability studies
Resolution-RE N1.of July 29th 2005
Central America
Untitled
Resolution No
China
Guidelines for stability testing of
drug substances and preparations
Chinese Pharmacopoeias Appendix 211
Costa Rica
Regulation for the medicine stability studies
Ministry o Health Executive decree No S dated 28/05/2007
Mexico
Stability of drugs and medicines
Official Mexican Standards nom -073 ssa1-2005
Nepal
Guidelines on stability of Pharmaceutical products
Guidelines issued on Friday, Asadh1.2054(June )
Panama
Ministry o Health Executive decree No.504( dated 9 November 2005)
Saudi Arabia (Saudi Foods & Drugs authority
Guidelines for stability testing of ne w drug substances
May 2005
South Africa (medicines Control Council)
Stability
Version 4 April 2009.
Date o implementation
1 July 2010
WHO Eastern Mediterranean Region
Stability testing of Active substances and pharmaceutical products
Draft 2.0
19 April 2005

40. variations and changes: guidelines
Importance of Revised Product stability Several types of post approval variations and changes are possible
Stability work up from nil to complete, dependent upon the type of change to a marketing authorization
variations and changes: guidelines
CPMP: Note on guidance on stability testing for a type II variation to a marketing authorization, April 1998
USFDA Draft Guidance for Industry: Stability Testing for drug substances and drug products, June 1998
Australian TGA 1994,: Appendix 8
WHO Draft, 2007
Nature of Changes
Internally driven
Changes in package design
The addition of a new package
Changing the shape and size o dosage forms
Changes in manufacturing process, etc.
Externally Driven
Deletion of dyes, Regulatory restrictions on formulation ingredients, Formulation Changes

41. Types of Post Approval Changes (US FDA)
STABILTY STUDIES
Types of Post Approval Changes (US FDA)
Changes in manufacturing process and/or equipment for the drug substance and the drug product
Change in the formulation of the drug product
Change in container and closure o the drug product
Change in manufacturing site
Addition of a new strength for the drug product
Change in batch size of the drug product
Reprocessing of a drug product
Changes in the stability protocol
A Basic Requirement: All Changes should be Accompanied by the standard stability commitment to conduct and/or complete long term stability studies on the first 1 or 3 bathes of the drug substance an/or drug product and annual batches thereafter. In accordance with the approved stability protocol
Relaxation: If the data gives no reason to believe that the proposed change will alter the stability of the drug product, the previously approved expiration dating period can be used.

42. STABILITY STUDIES
Basic principles for working on Revised product stability Selection of batches As per guidance Test criteria corresponding to original formulation Analytical procedure Specification Packing material Storage conditions and sampling frequency Long term storage Conditions: 6 month upto shelf life Accelerated: 0, 1, 3 and 6 months Intermediate: 3 and 6 months Evaluation: Results compared with original formulation Shelf life: if changed formulation is less stable , shelf life shortened accordingly

43. Minimum data requirements for submission- Drug products Generics USA: 3 months accelerated plus available RT for batch (study at intermediate condition may also be valuable) Canada: 6 months intermediate condition plus proposed shelf life RT for 2 batches EU: 6 months accelerated, 6 month intermediate condition, plus 6 months RT for 2 or 3 batches Since US ANDA registration requires only a single batch for tentative expiry dating ,statistical valuation generally can not be performed IN the US extrapolation of expiry dating to 24 months is based on satisfactory accelerated study plus available RT data Matrixing opportunity for generic applications although possible, like wise are limited in the US EU and canada follow ICH Q1E, matrixing and bracketing are possible

44. STABILTY STUDIES
Thank You…!!!