By

S.SANATH KUMAR
M. Pharm(Pharmaceutics), 1st semester,
JAYAMUKHI COLLGE OF PHARMACY
Content
s
 Introduction
 ICH guidelines over view
 Stability protocols for drug products(ICH
Q1A guidelines)
 Test parameters for different dosage forms
 Reference
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
 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
 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.
 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
 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
 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
 The Four Climatic Zones
Climatic Zone Definition Storage
conditions
I Temperature 210c/45%r.h.
climate
II Subtropical 250c/60%r.h.
and
Mediterranean 0
III climate 30 c/35%r.h.
Hot, dry
IV climate 300c/70%r.h.
Hot, humid
climate
 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.
 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.
 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
 Covering clinical safety, Dose response
Studies, Good clinical practices, Clinical
evolutions.
 “M” – Multidisciplinary Guidelines
Covering medical Terminology,
Electronic standards for Transmission of
Regulatory information.
 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
 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
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.
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
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
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.
 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 individual strength and container size
of the drug product unless bracketing or
matrixing is applied.
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
 5.Specifications:

• 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.
 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
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,
• Accelerated
48, 60 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
 • Intermediate storage condition
studies
ominimum four time points, including
initial
and final e.g.: 0,6,9,12 months, at time
of
o reduced designs, (matrixing or bracketing)
• Reduced design
submission 0,6 months
where
the testing frequency is reduced or certain
factor
combinations are not tested at all, can be
applied
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
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
o theAlabel storage condition
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
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.
 Drug products - In general
case
Study Storage Minimum time
condition period covered by
data at
submission
Long term 250c 12 months
+20c/60%r.h
Or
300c
+20c/65%r.h
intermediat 300c 6 months
e +20c/65%r.h
Drug products – packed in
semi permeable container
Study Storage Minimum time
condition period covered by
data at
submission
Long term 250c 12 months
+20c/40%r.h
Or
300c
+20c/35%r.h
intermediat 300c 6 months
e +20c/65%r.h
Drug products – intended
for storage in a refrigerator

Study Storage Minimum time

condition period covered
by data at
submission
Long term 50c + 30c 12 months

accelerated 250c + 20c 6 months

Drug products – intended
for storage in a freezer

Study Storage Minimum time

condition period covered
by data at
submission
Long term 200c + 50c 12 months
 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 required
not necessary
Submission
Submission doesincludes data data
not includes on three
from
production
three
batches covering proposed
production batches, shelf life
commitment to
continue through
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
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.
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.
 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.
 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.
 EMULSION: appearance, color, odour, assay ,
viscosity, microbial growth.
 SUSPENSION: particle size, appearance, color,
odour, preservative content, microbial growth,
re-dispersbility.
 SOLUTIONS: appearance, color, odour, pH,
viscosity, microbial growth, sterility.
 PARENTERALS: appearance, color, assay,
sterility (pyrogenicity or bacterial endotoxin),
impurities.
 IMPLANTS: total drug substance
content,
in-vitro drug release rate, sterility.
 TRANSDERMAL: appearance, assay,
leakage, microbial growth, drug
release rate.
 REFERENCE
 Guidelines on cGMP and quality of
pharmaceutical products by S.Iyer.
 Futscher, N.; Schumacher ,P.; Pharm. Ind. 34, 479
- 483 (1972)
 Grimm, W.; Krummen, K.; Stability Testing in the
EC, Japan and the USA,
 Wissenschaftiche Verlagsgesellschaft mbH,
Stuttgart (1993)
 Grimm, W.; Drugs made in Germany 28, 196 -
202 (1985) and 29, 39 - 47 ( 1986)
 Dietz, R.; Feilner, K., Gerst, F.; Grimm, W.; Drugs
made in Germany 36, 99 - 103,(1993)
 Haynes, J.D.; J. Pharm. Sci. 60, 927 - 929 (1971)
 www.ich.org
Thank
you !...........