ICH-guidlines for stability testing of drugs

Stability parameters

1. Dr.Y. SHIVA KUMAR
M.PHARM,PhD
Professor &HOD
Department of Pharmaceutics

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 ZoneDefinition Storage
conditions
I
II
III
IV
Temperature
climate
Subtropical and
Mediterranean
climate
Hot, dry climate
Hot, humid
climate
21
0
c/45%r.h.
25
0
c/60%r.h.
30
0
c/35%r.h.
30
0
c/70%r.h.

10. ICH guidelines over view
In1980
Harmonizationofregulatoryrequirementswas
pioneeredbytheEuropeancommunity,asthe
Europeanunionmovedtowardsthedevelopment
ofasinglemarketforpharmaceuticals
Atthesametimetherewerebilateraldiscussions
betweenEurope,JapanandtheUSonpossibilities
forharmonization.
In1989
AttheWHOconferenceofDrugRegulatory
Authorities(ICDRA),inParis,specificplansfor
actionbegantomaterialize.

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
Themanufacturerofthepharmaceuticalproductconfirms
thattheactivesubstancecomplieswiththe
pharmacopoeialmonographimmediatelypriortothe
manufactureofthepharmaceuticalproduct.Inthiscase
nostabilitystudiesontheactivesubstancearerequired.

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 individual
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. Itisbasedonallavailablestabilityinformation
Wherenecessarythejustificationforthelimitsproposed
forcertainothertestsasparticlesizeordissolutionrate
willrequirereferencetotheresultsobservedin
bioequivalenceorclinicalstudies.
Anydifferencesbetweenthereleaseandshelflife
specificationsforantimicrobialpreservativeshouldbe
supportedbypreservativeeffectivenesstesting
Singleprimarybatchshouldbetestedforantimicrobial
preservativeeffectivenessatproposedshelflife

24. 6. Testing frequency:
•Long term studies
ofirst year every three months. 0, 3, 6, 9, 12
osecond year every six months: 12, 18, 24
othird year and longer annually: 24, 36, 48, 60
•Accelerated studies
ogeneral minimum three time points: 0,3,6
months
oexpectation of significant change increases
testing adding samples at final time point or
forth time point: 0, 1, 3, 6 months

25. oreduced 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
ominimum 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.Storageconditions:
oStorageshouldbeevaluatedunderstorageconditions
thattestthermalstabilityand,ifapplicable,sensitiveto
moisture
oThestorageconditionsandthelengthsofstudies
chosenshouldbesufficienttocoverstorage,shipment,
andsubsequentuse
oThelongtermtestingshouldbecoveraminimumof
12months’durationonatleastthreeprimarybatches
oShouldbecontinuedtocoverproposedshelflife

27. oDatafromtheacceleratedstorageconditionand,if
appropriate,fromtheintermediatestorageconditioncan
beusedtoevaluatetheeffectofshorttermexcursionsout
sidethelabelstoragecondition
oAsignificantchangeinwaterlossaloneduring6months
acceleratedtestingdoesnotnecessitatestorageatinter-
mediatecondition,butnosignificantwaterloss
at25°C/40%.
oA significant change is a 5% water loss after 3 months
accelerated testing

28. oForsmallcontainers(1mlorless)morethan5%loss
after3monthsmaybeappropriate
oStorageundergeneralstorageconditionsandcalculate
waterlossdeterminingpermeationcoefficientorusing
calculatedratioofwaterloss.

29. Study Storage conditionMinimum time period
covered by data at
submission
Long term25
0
c +2
0
c/60%r.h
Or
30
0
c +2
0
c/65%r.h
12 months
intermediate30
0
c +2
0
c/65%r.h6 months
Accelerated40
0
c +2
0
c/75%r.h6 months
Drug products -In general case

30. Drug products –packed in semi
permeable container
Study Storage conditionMinimum time period
covered by data at
submission
Long term25
0
c +2
0
c/40%r.h
Or
30
0
c +2
0
c/35%r.h
12 months
intermediate30
0
c +2
0
c/65%r.h6 months
Accelerated40
0
c +2
0
c/25%r.h6 months

31. Drug products –intended for storage
in a refrigerator
Study Storage conditionMinimum time
period covered by
data at submission
Long term5
0
c +3
0
c 12 months
accelerated25
0
c +2
0
c 6 months

32. Drug products –intended for storage
in a freezer
Study Storage conditionMinimum time
period covered by
data at submission
Long term20
0
c +5
0
c 12 months

33. 8. Stability commitment
•Proposedshelflifenotcovered
Whenlongtermstabilitydatadonotproposedshelf
lifegrantedattimeofapproval,acommitmentshould
bemadetocontinuethestabilitystudiespostapprovalto
establishtheshelflife
•Commitmentnotnecessary
Submissionincludesdataonthreeproduction
batchescoveringproposedshelflife
•Commitmentrequired
Submissiondoesnotincludesdatafromthree
productionbatches,commitmenttocontinuethrough
proposedshelflife

34. oFewerthanthreeproductionbatchescommitment
continuewiththesestudiesthroughproposedshelflife
andplaceadditionalbatchestoatotalofthreeonlong
termandacceleratedstabilitytestingthroughproposed
shelflife.
oThestabilityprotocolusedforstudiesoncommitment
batchesshouldbethesameasthatfortheprimary
batches

35. 9. Evaluation
oToestablishshelflifeandstorageinstructionsapplicable
forallfurtherbatchesmanufacturedandpackedunder
similarcircumstances.
oSystematicapproachinpresentationandevaluationof
stabilityinformation.
oShouldincluderesultsfromphysical,chemical,biological
andmicrobiologicaltests.

36. oThebatchtobatchvariabilityisifsmall,itis
advantageoustocombinethedataintooneoverall
estimate
oIfitisinappropriatetocombinedatafromseveral
batches,theoverallshelflifeshouldbebasedonthe
minimumtimeabatchcanbeexpectedtoremainwithin
acceptancecriteria
oAnyevolutionshouldcovernotonlytheassay,butalso
thelevelsofdegradationproductsandotherappropriate
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.

39. 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.

40. IMPLANTS: total drug substance content,
in-vitro drug release rate, sterility.
TRANSDERMAL: appearance, assay, leakage,
microbial growth, drug release rate.

41. 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

42. Thank you !...........