pharmceutical analysis m.pharm advanced pharmaceutical analysis

1. KARNATAKA COLLEGE OF PHARMACY
Seminar topic: STABILITY STUDIES AND ICH-GUIDELINES
By: KAVANA BB
1ST SEM M Pharm
Subject : APA
DEPARTMENT OF PHARMACEUTIAL ANALYSIS SUBMITTED TO:DR.C .SREEDHAR
HOD AND PROFESOR
DEPARTMENT OF PHARMACEUTICAL ANALYSIS
KARNATAKA COLLEGE OF PHARMACY 1

2. CONTENT:
• INTRODUCTION
• SCOPE
• ADVANTAGES
• ACCLERATED STABILITY TESTING
• GUIDELINES FOR STABILITY STUDIES
KARNATAKA COLLEGE OF PHARMACY 2

3. STABILITYTESTING
• Stability : defined as capability of a particular formulation in specific
Container/closure system to remain within its physical,chemical,
microbiological, toxicological, protective and informal specifications.
• It is the extent to which a product retains, within the specifiedlimits,
throughout its period of storage and use, the same properties and
characteristics possessed at the time of its packaging.
KARNATAKA COLLEGE OF PHARMACY 3

4. SCOPE OF STABILITY STUDIES
• Provide as to how the quality of drug product varies with time.
• Establish shelf life of drug product.
• Determine recommended storage conditions.
• Determine container closure system suitability
KARNATAKA COLLEGE OF PHARMACY 4

5. IMPORTANCE OF STABILITY STUDIES
• Assurance to patient that drug is safe.
• Legal requirement to provide data.
• To protect the reputation of the manufacture.
• To provide a database.
• To determine shelf life and storage conditions.
• To verify that no changes have been introduced in the formulation or
manufacturing process that can adversely affect the stability of the
product
KARNATAKA COLLEGE OF PHARMACY 5

6. TYPES OF STBILITY STUDIES
• CHEMICAL
• PHYSICAL
• MICROBIOLOGICAL
• THERAPEUTIC
• TOXICOLOGICAL
KARNATAKA COLLEGE OF PHARMACY 6

7. STABILITY STUDIES METHOD
• REAL TIME TESTING
• ACCELERATED STABILITY TESTING
• RETAINED SAMPLE STABILITY TESTING
• CYCLIC TEMPERATURE STRESS TESTING
KARNATAKA COLLEGE OF PHARMACY 7

8. REAL TIME TESTING
Date collected at appropriate frequency
To distinguish Instability from day to day
Stability of reference material include the stability of reagent as well as
consistency of performance
KARNATAKA COLLEGE OF PHARMACY 8

9. RETAINED SAMPLE STABILITY TESTING
• Usual practice for every marketed product for which stability data are require. Only
one batch a year are selected. If the number of batches marketed exceeds 50,
stability sample from two batches are recommended to be taken.
• Stability testing by evaluation of market samples is a modified method which
involve taking samples already in the market place and evaluating stability
attributes
KARNATAKA COLLEGE OF PHARMACY 9

10. CYCLIC TEMPERATURE STRESS TESTING
• Is not a routine testing method for marketed products
• In this method, cyclic temp. stress tests are designed on knowledge of the product so as
to mimic likely condition in market place storage.
• The period of cycle mostly considered is 24 hours.
• The min. and max. temp. for the cyclic stress testing is recommended to be selected ona
product by – product basis and considering factors like recommended storage temp.
for the product and specific chemical and physical degradation properties of the
products.
• The test should normally have 20 cycles.
KARNATAKA COLLEGE OF PHARMACY 10

11. ACCELERATED STABILITY TESTING
A product is stressed at several high temp. & the amount of heat inputrequired to cause
product failure is determined.
• This is done to subject the product to a condition that acceleratesdegradation
• This information is then projected to predicted to predict shelf life orused to compare the relative
stability of alternative formulations
Samples subjected to stress
Refrigerated
Assayed Simultaneously
KARNATAKA COLLEGE OF PHARMACY 11

12. GUIDELINE FOR STABILITY TESTING
ICH CODE
GUIDELINE TITLE
QIA Stability testing of New Drug Substances and Products(Second Revision)
QIB Stability testing : Photo stability testing of New Drug
Substances and Products
QIC Stability testing of New Dosage Form
QID Bracketing and Matrixing Designs for stability testing of drugsubstances and Products
QIE Evaluation of stability data
QIF Stability data package for Registration Applications inClimatic Zones III and IV
Q5C Stability testing of Biotechnological/Biological Products
KARNATAKA COLLEGE OF PHARMACY 12

13. STABILITY ZONES
KARNATAKA COLLEGE OF PHARMACY 13

14. KARNATAKA COLLEGE OF PHARMACY 14

15. PHOTOSTABILITY TESTING
KARNATAKA COLLEGE OF PHARMACY 15

16. ICH-GUIDELINE FOR BIOLOGICAL PRODUCTS
KARNATAKA COLLEGE OF PHARMACY 16

17. 1) SELECTION OF BATCHES
DRUG SUBSTANCE(BULK MATERIAL)
• A bulk material after the manufacture has to be stored however prior to formulation and manufacture.
• Stability data should be provided on at least 3 batches for which manufacture and storage are representative of
the manufacturing scale of production.
• A minimum of six months stability data at the time of submission should be submitted in cases where storage
periods are greater than 6 months are requested.
• For a drug substance with storage periods of less than 6 months minimum amount of stability data in the initial
submission should be determined on case by case basis.
• Data from pilot plant scale batches of drug substance produced at a reduced scale of fermentation and
purification may be provided at the time the dossier is submitted to regulatory agencies with the commitment
to place the 1st three manufacturing scale batches into the long stability program.
KARNATAKA COLLEGE OF PHARMACY 17

18. INTERMEDIATE
During manufacture of biotechnological/ bioligical products, the quality and control of
intermediates may be critical to the production of the final product.
In general, manufacturer should identify intermediates and generate in house data and process
limits that assures their stability within the bounds of the developed process. While the pilot plant
scale data is permissible, the manufacturer establish the suitability of such data using
manufacturing scale process
KARNATAKA COLLEGE OF PHARMACY 18

19. STABILITY PRODUCT (FINAL PRODUCT)
• Stability information should be provided on at least 3 batches of final container product
representative of that which will be used in manufacturing scale.
• A minimum of six months data at the time of submission should be submitted in cases
when storage periods greater than six months are requested.
• For drug products with storage periods less than 6 months, the minimum amount of
stability data in the initial should be determined in a case by case studies.
• Product expiration dating will be based upon the actual data the actual data submitted in
support of the application.
• The quality of the final container product placed on stability studies should be
representative of the quality of material used in preclinical and clinical studies.
KARNATAKA COLLEGE OF PHARMACY 19

20. 2) SAMPLE SELECTION
• one product is distributed in batches differing in fill volumes ( eg ; 1 ml, 2 ml, 10
ml), unitage (10 units, 20 units, or 50 units) or mass ( eg ; 1 mg, 2 mg, 5 mg)
samples to be entered into the suitability program may be selected on the basis
of a matrix system and /or by bracketing.
• Bracketing is the design of a stability schedule such that only samples on the
extremes of certain design factors (e.g., strength, container size and/or fill) are
tested at all time points as in a full design. The design assumes that the stability
of any intermediate levels is represented by the stability of the extremes tested.
• The use of a bracketing design would not be considered appropriate if it cannot
be demonstrated that the strengths or container sizes and/or fills selected for
testing are indeed the extremes.
KARNATAKA COLLEGE OF PHARMACY 20

21. 3) STABILITY INDICATING PROFILE
• On the whole, there is no single stability – indicating assay or parameter that
profiles the stability characteristics of a biotechnological/biological products.
• Consequently, the manufacturer should propose a stability indicating profile that
provides assurance that changes in the identity, purity, and potency of the product
will be detected.
• At the time of submission applicants should have validated the method that
comprise the stability indicating profile and the data should be available for the
review.
KARNATAKA COLLEGE OF PHARMACY 21

22. a) PROTOCOL: The dossier accompanying the application for marketing
authorization should include a detailed protocol for the assessment for the
stability of both drug substance and drug product.
b) POTENCY: Potency studies are to be performed at appropriate intervals as
defined in the stability protocol and the results should be represented in units
of biological activity calibrated, whenever possible, against nationally and
internationally standards
KARNATAKA COLLEGE OF PHARMACY 22

23. C) PURITY AND MOLECULAR CHARACTERISATION:
• For the purpose of stability testing of the products described in the guideline,
purity is a relative term.
• Due to the effect of glycosylation, deamination or other heterogeneities, the
absolute purity of a biotechnological/biological product should be typically
assessed by more than one method and the purity value desired is method
dependent.
• For the purpose of stability testing, tests for purity should focus on methods for
determination of degradation products.
KARNATAKA COLLEGE OF PHARMACY 23

24. 4) Storage conditions
• TEMPERATURE : Since most finished biotechnological/biological products need
precisely defined storage temperatures, the storage conditions for the real
time/real-temperature stability studies may be confined to the proposed storage
temperature.
• HUMIDITY : Biological products are generally distributed in containers protecting
them against humidity. Therefore, where it can be demonstrated that the
proposed containers (and conditions of storage) afford sufficient protection
against high and low humidity, stability tests at different relative humidities can
usually be omitted. Where humidity protecting containers are not used,
appropriate stability data should be provided.
KARNATAKA COLLEGE OF PHARMACY 24

25. • ACCELERATED AND STRESS CONDITION : Studies under accelerated and stress
conditions may provide useful support data for establishing the expiration date,
provide product stability information for future product development.
• LIGHT : Applicants should consult the appropriate regulatory authorities on a
case by case basis to determine guidance for testing.
• CONTAINER CLOSURE : The interaction of the product and container should not
result into degradation of product. Hence, a proper consideration has to be
undertaken to maintain the stability of the product.
KARNATAKA COLLEGE OF PHARMACY 25

26. 5) Testing frequency
• The shelf lives of biotechnological/biological may vary days to several years.
Thus, it is difficult to draft uniform guideline regarding the stability study
duration and testing frequency that would be applicable to all biotechnical and
biological products.
• However with few exceptions it is considered 0 to 5 years.
• When self lives of 1 year or less is proposed, the real time stability studies should
be conducted monthly for the first 3 months and at 3 months interval there after.
• For the product with proposed shelves life more than 1 year, the studies should
be conducted every three months during the first year of storage, every six
months during the second year and thereafter.
KARNATAKA COLLEGE OF PHARMACY 26

27. 6) LABELLING
• Precisely, definite temperature storage are recommended.
• Specific recommendation should be stated, particularly to those drug
products and drug substances that cannot tolerate freezing.
KARNATAKA COLLEGE OF PHARMACY 27

28. KARNATAKA COLLEGE OF PHARMACY 28