2. Contents
Introduction
ICH guidelines over view
Stability protocols for drug products(ICH
Q1A guidelines)
Test parameters for different dosage forms
Reference
3. What is ICH guidelines ?
International Conference on Harmonization of
Technical Requirements for Registration of
Pharmaceuticals for human use
ICH is a joint initiative involving both regulators
and industry as equal partners in the scientific and
technical discussions of the testing procedures
4. There are six parties directly involved in the decision making
process
EU : European commission – European union
EFPIA : European Federation of Pharmaceutical
Industries and Associations
MHLC : Ministry of Health ,Labor and Welfare, Japan
JPMA : Japan Pharmaceutical Manufacturers
Associations
FDA : US Food and Drug Administration
PhRMA : Pharmaceutical Research and Manufacturers
of America
5. Why the ICH guidelines?
Harmonization of registration applications with in
the three regions of the EU , Japan and the United
states
ICH aims to produce a single set of technical
requirements for the registration of drug products
and hence the development process
To ensure and assess the safety, quality and efficacy
of medicines.
6. What and Why the stability ?
Defined as the capability of a particular formulation in a
specific container to remain within it’s physical, chemical,
microbiological specifications throughout its shelf life
Evidence of Quality of the drug substance or drug
product
And provides how Quality of the drug substance or
product varies with time under the influence of a variety of
environmental factors such as
Temperature
Humidity
light
7. In addition, product-related factors influence the stability,
e.g. the chemical and physical properties of the active
substance and the pharmaceutical excipients, the dosage form
and its composition, the manufacturing process, the nature of
the container-closure system etc.
Establish re test period for drug substances
Establish shelf life for drug products
Recommend storage conditions
Test conditions based on analysis of effects of climatic
conditions in three regions of the EC, Japan and USA
World can thereby divided in to four climatic zones I-IV
8. Countries of climatic zone I&II:-
• Europe: all countries
• America: Argentina, Bolivia, Canada, Usa
• Asia: Armenia, China, Iran, Japan, Korea, Nepal
• Africa: Egypt, Libya, Namibia, Zambia, southafrica
• Australia: Australia&Newzeland
Countries of climatic zone III&IV:-
• America: Bahamas, Belize, Brasilia, Costa rica,
Colombia
• Asia: India, Bangladesh, Iraq, Kuwait, Thailand, UAE
• Africa: Angola, Ethiopia, Benin, Botswana
9. The Four Climatic Zones
Climatic Zone Definition Storage
conditions
I
II
III
IV
Temperature
climate
Subtropical and
Mediterranean
climate
Hot, dry climate
Hot, humid
climate
210c/45%r.h.
250c/60%r.h.
300c/35%r.h.
300c/70%r.h.
10. ICH guidelines over view
In 1980
Harmonization of regulatory requirements was
pioneered by the European community, as the
European union moved towards the development
of a single market for pharmaceuticals
At the same time there were bilateral discussions
between Europe, Japan and the US on possibilities
for harmonization.
In 1989
At the WHO conference of Drug Regulatory
Authorities (ICDRA), in Paris, specific plans for
action began to materialize.
11. In 1990
The birth of ICH took place at meeting in April
1990 in Brussels where Representatives of the
regulatory agencies of Europe, Japan and the USA.
12. Scope:
ICH produces guidelines which covers:
“Q” – Quality Guidelines
Concerned with stability, specifications and analytical
method validation
“S” – Safety Guidelines
In-vitro and In-vivo pre-clinical studies
Covering Carcinogenicity Testing, Genotoxicity Testing,
Toxicokinetics and pharmacokinetics
“E” – Efficacy Guidelines
Clinical studies in human subject
13. Covering clinical safety, Dose response Studies,
Good clinical practices, Clinical evolutions.
“M” – Multidisciplinary Guidelines
Covering medical Terminology, Electronic standards
for Transmission of Regulatory information.
14. ICH Q – Guidelines (Quality)
• Q1A - stability testing for drug substances or drug
products
• Q1B – photo stability testing
• Q1C – stability testing for new dosage forms
• Q1D – Bracketing and Matrixing designs
• Q1E – Evaluation of stability data
• Q1F – stability testing in climatic zone III & IV
• Q2 – validation of Analytical procedures
• Q3 – Impurities
• Q4 – pharmacopiel harmonization
• Q5 – Biotechnological products
• Q6 - Specifications
15. Stability protocols for drug products:
1. General
2. Photo stability testing
3. Selection of batches
4. Container closure system
5. Specifications
6. Testing frequency
7. Storage conditions
8. Stability commitment
9. Evaluation
10. labeling
16. 1.General:
The design of stability studies should be based on
knowledge of the
Behavior and
Properties of the drug substance
The manufacturer of the pharmaceutical product confirms
that the active substance complies with the
pharmacopoeial monograph immediately prior to the
manufacture of the pharmaceutical product. In this case
no stability studies on the active substance are required.
17. 2.Photo stability testing:
Testing should be conducted on at least one batch
Photo stability characteristics of drug products
should be evaluated to demonstrate that light
exposure does not result in unacceptable change
Procedure
Tests on the exposed drug product out side of the
immediate pack
18. Tests on the drug products in the immediate pack
Tests on the drug product in the marketing pack
By using an integrated near ultraviolet energy of not
less than 200 watt hours/square meter
19. 3. Selection of batches:
At least three primary batches of the drug product
are required
Same formulation and in same container closure system
as proposed for marketing
The manufacturing process used for primary batches
should simulate that to be applied to production batches
Same quality and meeting specifications as that intended
for marketing
That at least the first two production scale batches
manufactured should be long-term stability studies.
20. Two of three batches at least pilot scale third can be
smaller
Drug products should be manufactured by using
different batches of the drug substances
Stability studies should be performed on each individua
strength and container size of the drug product unless
bracketing or matrixing is applied.
21. 4.Container closure system:
the testing should be carried out in the final packaging
proposed for marketing
Additional testing of unprotected finished product can
form a useful part of the stress testing
Or other packaging materials can form a useful part of
the stress testing of the dosage form
22. • The non-pharmacopoeial products should be derived
from acceptable and justifiable derivations from
release specifications based on the stability
evaluation and changes observed on storage.
• attributes susceptible to change during storage
• may influence quality, safety and/or efficacy
• should cover physical, chemical, biological,
microbiological attributes.
5.Specifications:
23. It is based on all available stability information
Where necessary the justification for the limits proposed
for certain other tests as particle size or dissolution rate
will require reference to the results observed in
bioequivalence or clinical studies.
Any differences between the release and shelf life
specifications for antimicrobial preservative should be
supported by preservative effectiveness testing
Single primary batch should be tested for antimicrobial
preservative effectiveness at proposed shelf life
24. 6. Testing frequency:
• Long term studies
o first year every three months. 0, 3, 6, 9, 12
o second year every six months: 12, 18, 24
o third year and longer annually: 24, 36, 48, 60
• Accelerated studies
o general minimum three time points: 0,3,6
months
o expectation of significant change increases
testing adding samples at final time point or
forth time point: 0, 1, 3, 6 months
25. o reduced designs, (matrixing or bracketing) where
the testing frequency is reduced or certain factor
combinations are not tested at all, can be applied
• Intermediate storage condition studies
o minimum four time points, including initial
and final e.g.: 0,6,9,12 months, at time of
submission 0,6 months
• Reduced design
26. 7. Storage conditions:
o Storage should be evaluated under storage conditions
that test thermal stability and, if applicable, sensitive to
moisture
o The storage conditions and the lengths of studies
chosen should be sufficient to cover storage, shipment,
and subsequent use
o The long term testing should be cover a minimum of
12 months’ duration on at least three primary batches
o Should be continued to cover proposed shelf life
27. o Data from the accelerated storage condition and, if
appropriate, from the intermediate storage condition can
be used to evaluate the effect of short term excursions out
side the label storage condition
o A significant change in water loss alone during 6 months
accelerated testing does not necessitate storage at inter-
mediate condition, but no significant water loss
at25°C/40%.
o A significant change is a 5% water loss after 3 months
accelerated testing
28. o For small containers (1 ml or less) more than 5% loss
after 3 months may be appropriate
o Storage under general storage conditions and calculate
water loss determining permeation coefficient or using
calculated ratio of water loss.
29. Study Storage condition Minimum time period
covered by data at
submission
Long term 250c +20c/60%r.h
Or
300c +20c/65%r.h
12 months
intermediate 300c +20c/65%r.h 6 months
Accelerated 400c +20c/75%r.h 6 months
Drug products - In general case
30. Drug products – packed in semi
permeable container
Study Storage condition Minimum time period
covered by data at
submission
Long term 250c +20c/40%r.h
Or
300c +20c/35%r.h
12 months
intermediate 300c +20c/65%r.h 6 months
Accelerated 400c +20c/25%r.h 6 months
31. Drug products – intended for storage
in a refrigerator
Study Storage condition Minimum time
period covered by
data at submission
Long term 50c + 30c 12 months
accelerated 250c + 20c 6 months
32. Drug products – intended for storage
in a freezer
Study Storage condition Minimum time
period covered by
data at submission
Long term 200c + 50c 12 months
33. 8. Stability commitment
• Proposed shelf life not covered
When long term stability data do not proposed shelf
life granted at time of approval, a commitment should
be made to continue the stability studies post approval to
establish the shelf life
• Commitment not necessary
Submission includes data on three production
batches covering proposed shelf life
• Commitment required
Submission does not includes data from three
production batches, commitment to continue through
proposed shelf life
34. o Fewer than three production batches commitment
continue with these studies through proposed shelf life
and place additional batches to a total of three on long
term and accelerated stability testing through proposed
shelf life.
o The stability protocol used for studies on commitment
batches should be the same as that for the primary
batches
35. 9. Evaluation
o To establish shelf life and storage instructions applicable
for all further batches manufactured and packed under
similar circumstances.
o Systematic approach in presentation and evaluation of
stability information.
o Should include results from physical, chemical, biological
and microbiological tests.
36. o The batch to batch variability is if small, it is
advantageous to combine the data in to one overall
estimate
o If it is inappropriate to combine data from several
batches, the overall shelf life should be based on the
minimum time a batch can be expected to remain with in
acceptance criteria
o Any evolution should cover not only the assay, but also
the levels of degradation products and other appropriate
attributes.
37. 10. labeling
A storage statement for labeling in accordance with
national/regional requirements
Statement based on the stability evaluation of the drug
product
A minimum temperature range or maximum temperature
range of storage must be specified(in degree Celsius) the
use of terms such as “room temp” is unacceptable.
An expiration date should be displayed on container label.
Some specific requirements like “protect from light” &
“protect from freezing” should be stated where applicable.
38. TEST PARAMETERS FOR
DIFFERENT DOSAGE FORMS:
TABLETS: appearance, color, odour, assay, weight
variation test, disintegration or dissolution, friabillity
or hardness testing.
CAPSULE: appearance, color, odour ,assay,
disintegration or dissolution , microbial growth.
ORAL POWDERS: appearance, color, odour,
moisture and re constitution time
SUPPOSITORY: appearance, color, particle size,
assay, dissolution, microbial growth.
