Performing Stability studies

Hyderabad, Mumbai, Ahmedabad - INDIA

March 24th, 26th, and 28th 2007

Ulrich Markens
Head of QC Testing Labs Asia
SGS Life Science Services
 FDA Warning Letter Report 2006

2005 2006 ∆

Drugs 17 20 18%
(part 211)

Blood, Blood products, Biologicals 9 10 11%

(part 600 606, 610, 630, 640, 680)

Medical devices 107 79 -26%

(part 820)

2
 FDA Warning Letter Report 2006 (cont’d)

Top 5 findings

3
Index

1 General Information

2 Examples for Stability testing design

3 Climatic Zones

4 ICH and Guidelines overview

5 ICH Q1A Guideline

6 Other relevant ICH Guidelines

7 Requirements for performing Stability studies

4
 Why Stability?

„ Provide a evidence on how the quality of a drug substance or

drug product varies with time under the influence of a variety of
environmental factors such as
• temperature,
• humidity,
• and light

„ Establish a
• re-test period for the drug substance or a
• shelf life for the drug product and
• recommended storage conditions
„ Because physical, chemical or microbiological changes might
impact the
• efficiency and
• security of the final product
*) Definition according to ICH Q1A(R2)

5
1 - General Information
 Where and Why?

Stability Studies are preformed on

„ Drug Substances (DS)
• … the unformulated drug substance that may subsequently be
formulated with excipients to produce the dosage form

„ Drug Products (DP)

• .. the dosage form in the final immediate packaging intended for
marketing

and represents

„ controlled and documented determination of acceptable

changes of the drug substance or drug product

6
1 - General Information
 What are changes?

„ Physical changes
• Appearance
• Melting point
• Clarity and color of solution
• Water
• Crystal modification (Polymorphism)
• Particle size

„ Chemical changes
• Increase in Degradation products
• Decrease of Assay

„ Microbial changes
• Growth of microorganism

7
1 - General Information
 Stability studies at different stages

1. Stress- and accelerated Testing with drug substances

2. Stability on pre-formulation batches
3. Stress testing on scale-up Batches
4. Accelerated and long term testing for registration
5. On-going Stability testing „ Scope
• Determination of expire date
6. Follow-up Stabilities •
•
Determination of preliminary specifications
Release of clinical batches
• Monitoring of samples during the clinical phases
„ Scope • Definition of storage conditions
• Solubility Profile
• Definition of Tests for registration stability
• Hygroscopicity
• Thermal stability „ Selection of samples
„ Up to 36 month Ad 3
•
(Melting point, Polymorphism) API, excipient, batches
• Chemical stability
„ Scope
„ 1 Batch • Appearance
„ Up to 3 month Ad
• 1 Appropriate physical-chemical parameter
• Assay / Degradation products
„ Up to 3 month Ad 2

8
1 - General Information
2 Examples for Stability testing designs

9
 Examples for stability testing designs

„ Testing scope for DRUG SUBSTANCES

• Physical-chemical properties
– Appearance
– Water content
– pH
– Color / clarity of solution
– Thermo analytical stability
» Melting point
» Polymorphism
• Chemical properties
– Assay
– Degradation products
• Microbial properties
– (Microbial purity)

10
2 - Examples for Stability testing design
 Examples for stability testing designs (cont’d)

„ Testing scope for TABLETS

• Physical-chemical properties
– Appearance
– Mean mass
– Water content
– Hardness
– Disintegration
– Dissolution
• Chemical properties
– Assay
– Degradation products
• Microbial properties
– Microbial purity
• Container closure system properties
– Functionality tests (e.g. extraction from blister)

11
2 - Examples for Stability testing design
 Examples for stability testing designs (cont’d)

„ Testing scope for CAPSULES

• Physical-chemical properties
– Elasticity
– Mean mass
– Mean filling mass
– Water content (Capsule and content)
– Disintegration
– Dissolution
• Chemical properties
– Assay
– Degradation products
• Microbial properties
– Microbial purity
• Container closure system properties
– Functionality tests (e.g. extraction from blister)

12
2 - Examples for Stability testing design
 Examples for stability testing designs (cont’d)

„ Testing scope for oral LIQUID FORMS

• Physical-chemical properties
– pH
– Color & clarity of solution
– Loss on weight
– Viscosity
– Particle size distribution (for oral suspensions only)
• Chemical properties
– Assay
– Degradation products
– Content preservatives
– Degradation preservatives
– Content antioxidants
• Microbial properties
– Microbial purity
• Container closure system properties
– Functionality tests

13
2 - Examples for Stability testing design
 Examples for stability testing designs (cont’d)

„ Testing scope for LIQUID FORMS for inj. and PARENTERALIA

• Physical-chemical properties
– pH
– Loss on weight
– Color & clarity of solution
• Chemical properties
– Assay
– Degradation products
– Content preservatives
– Degradation preservatives
– Content antioxidants
• Microbial properties
– Microbial purity
• Container closure system properties
– Functionality tests

14
2 - Examples for Stability testing design
 Examples for stability testing designs (cont’d)

„ Testing scope for SEMI LIQUID FORMS

• Physical-chemical properties
– Appearance, odor, homogeneity, consistency
– Loss on weight
– Viscosity
– Content uniformity (within the container)
• Chemical properties
– Assay
– Degradation products
– Content preservatives
– Degradation preservatives
– Content antioxidants
• Microbial properties
– Microbial purity
• Container closure system properties
– Functionality tests

15
2 - Examples for Stability testing design
3 Climatic Zones

16
 Climatic Zones / Storage conditions

Climatic Zone Calculated data Derived data

Countries Temp. MKT humidity Temp. humidity
°C °C % r.h. °C % r.h.

Climatic Zone I
"Temperate" 20 20 42 21 45
Japan, United Kingdom, Northern Europe,
Canada, Russia, United States

Climatic Zone II
"Mediterranean, Subtropical" 21,6 22 52 25 60
Japan, United States, Southern Europe

Climatic Zone III

"Hot, dry" 26,4 27,9 35 30 35
Iran, Iraq, Sudan

Climatic Zone IV
"Hot, humid" 26,7 27,4 76 30 70
Brazil, Ghana, Indonesia, Nicaragua,
Philippines

*) Table taken from USP28 – NF23, General chapter <1150>

17
3 – Climatic Zones
 Countries of climatic zone I and II

„ Europe
• all countries
„ Americas
• Argentina, Bolivia, Chile, Canada, Peru, USA, Uruguay …
„ Asia
• Afghanistan, Armenia, Aserbaidschan, China, Georgia, Iran,
Israel, Japan, Corea (north & south), Lebanon, Nepal, Syria,
Turkey …..
„ Africa
• Egypt, Algeria, Libya, Marocco, Namibia, Ruanda, Sambia,
Simbabwe, South Africa, Tunesia …
„ Australia
• Australia, New Zeeland

18
3 – Climatic Zones
 Countries of climatic zone III and IV

„ Americas
• Bahamas, Barbados, Belize, Brasilia, Costa Rica, Ecuador,
Guatemala, Colombia, Nicaragua …
„ Asia
• Bahrain, Bangladesh, India, Indonesia, Iraq, Cambodia,
Qatar, Kuwait, Laos, Malaysia, Myanmar, Pakistan,
Philippines, Singapore, Thailand, UAE, Vietnam …..
„ Africa
• Angola, Ethiopia, Benin, Botswana, Burkina Faso …..
„ Oceania
• Fiji, Marshall Islands, Micronesia, Papua New-Guinea ….

19
3 – Climatic Zones
4 ICH and Guidelines overview

2 Examples for Stability testing design

3 Climatic Zones

4 ICH and Guidelines overview

5 ICH Q1A Guideline

6 Other relevant ICH Guidelines

7 Requirements for performing Stability studies

20
 What or Who is ICH?

„ ICH stands for International Conference on Harmonization of

Technical Requirements for Registration of Pharmaceuticals for
Human use

„ Objectives of ICH
• Harmonization of registration applications within the three regions of
the EU, Japan and the United States.
• ICH is a joint initiative involving both regulators and industry as equal
partners in the scientific and technical discussions of the testing
procedures which are required to ensure and assess the safety,
quality and efficacy of medicines

21
4 – ICH and Guidelines overview
 What or Who is ICH?

„ There are Six Parties directly involved in the decision making

process
• EU: European Commission - European Union
• EFPIA: European Federation of Pharmaceutical Industries and
Associations
• MHLW: Ministry of Health, Labor and Welfare, Japan
• JPMA: Japan Pharmaceutical Manufacturers Association
• FDA: US Food and Drug Administration
• PhRMA: Pharmaceutical Research and Manufacturers of America
„ There are additionally observers installed to act as a link with
non-ICH countries and regions
• WHO
• The European Free Trade Area (EFTA),
represented by Swissmedic Switzerland
• Health Canada

22
4 – ICH and Guidelines overview
 A brief History of ICH

„ 1980s
• Harmonization of regulatory requirements was pioneered by the
European Community, as the European Union moved towards the
development of a single market for pharmaceuticals.
• The success achieved in Europe demonstrated that harmonization
was feasible.
• At the same time there were bilateral discussions between Europe,
Japan and the US on possibilities for harmonization.
„ 1989
• At the WHO Conference of Drug Regulatory Authorities (ICDRA), in
Paris, specific plans for action began to materialize.
„ 1990
• The birth of ICH took place at a meeting in April 1990 in Brussels
where Representatives of the regulatory agencies and industry
associations of Europe, Japan and the USA met

23
4 – ICH and Guidelines overview
 Guidelines

„ ICH Guidelines
• Quality Guidelines “Q” (chemical and pharmaceutical QA)
– details see next slide
• Safety Guidelines “S” (in vitro and in vivo pre-clinical studies)
– covering Carcinogenicity Testing, Genotoxicity Testing,
Toxicokinetics and Pharmacokinetics ….. etc.
• Efficacy Guidelines “E” (clinical studies in human subject)
– Covering clinical safety, Dose Response Studies, Good Clinical
Practices, Clinical evaluation …. etc.
• Multidisciplinary Guidelines “M”
– Covering Medical Terminology, Electronic Standards for
Transmission of Regulatory Information …… etc.
– Important for Stability !
» Guideline M4: The Common Technical Document (CTD)

24
4 – ICH and Guidelines overview
 Guidelines

„ ICH Q-Guidelines (Quality)

• Stability Testing in Climatic Zone I and II (Q1A)

• Photostability Testing (Q1B)
• Stability Testing for New Dosage Forms (Q1C)
• Bracketing and Matrixing Designs (Q1D)
• Evaluation of Stability Data (Q1E)
• Stability Testing in Climatic Zones III and IV (Q1F)
• Validation of Analytical Procedures (Q2)
• Impurities (Q3)
• Biotechnological Products (Q5)
• Specifications (Q6)

25
4 – ICH and Guidelines overview
 Guidelines

„ ASEAN* Guidelines
• Stability Studies of Drug products
• Validation of Analytical Procedures
• Common Technical Dossier (ACTD) for the registration of
pharmaceuticals

„ FDA (Food and Drug Administration)

• Guidance for Industry: Stability Testing of Drug Substances and Drug
F DA
Products; June 1998
n by 6
– One fits all document raw 200
– Considers ICH Q1A, i tQ1B, ne and Q5C
hd uQ1C
W In J

* ASEAN Members: Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, Vietnam

26
4 – ICH and Guidelines overview
 Guidelines

„ WHO
• WHO TRS 863, Annex 5: “Guidelines for stability testing of
pharmaceutical products containing well established drug substances
in conventional dosage forms”
„ USP (US Pharmacopeia)
• USP 29 <1150> Pharmaceutical Stability
„ EMEA (European Agency for the Evaluation of Medicinal Product)
• Note for Guidance on Stability Testing of existing active substance
and Related Finished products (Draft), February 2002
„ etc.

27
4 – ICH and Guidelines overview
 Guidelines
Bracketing and Matrixing
Evaluation of Stability Data

Q1D
ICH
Q1D
New Dosage Forms

ICH
IC
QQ1
ICHH

ICICH
Q1H
1EE

1CC
Analytical Validation

Q
ICI
QQ CHH Stability Testing of New DS and DP
22 (Climatic Zone I and II) Biotechnological Products

HH
ICH
ICH Q1A
Q1A ICC
I 5
QQ5

WHO
WHO FDA
FDA
ICHH
IC
QQ11FF
ASEAN
ASEAN ICI
Stability Testing QQ1 CHH
in Climatic Zones III and IV 1BB

I ICH
QQ3 C H Impurities H
Photostability Testing
3AA/B Specifications ICICH/BB
/B/C A/
/C QQ66A
28
4 – ICH and Guidelines overview
5 ICH Q1A Guideline

29
 ICH Q1A Guideline

„ Objectives
• Define common principles valid for both Drug Substances and
Products
• Ensures that all data derived from DS can be used for further
development of DP

„ Scope
• Adresses the information to be submitted in registration applications
for
– new molecular entities (NMEs) and
– Associated drug products
• Dedicated to climatic Zone I and II
• Does not currently seek to cover the information to be submitted for
– abbreviated or abridged applications
– variations
– clinical trial applications

30
5 – ICH Q1A Guideline
 Structure / Sections

1. General
2. Stress Testing
• Comprehensive Stress testing for Drug Substances
• Photostability for Drug products
3. Selection of batches
4. Container closure system
5. Specifications
6. Testing frequency
7. Storage conditions
8. Stability commitment
9. Evaluation
10. Statements / Labeling

31
5 – ICH Q1A Guideline
 Section 1 - General

„ Drug Substance
• Information on the stability of the drug substance is an integral part of the
systematic approach to stability evaluation

„ Drug Product
• The design of the stability studies should be based on knowledge of the
– behavior and
– properties of the drug substance and from
– stability studies on the drug substance and on
– experience gained from clinical formulation studies.
• The likely changes on storage and the rationale for the selection of attributes to
be tested in the formal stability studies should be stated

32
5 – ICH Q1A Guideline
 Section 2 - Stress Testing

„ Drug Substance
• carried out on a single batch
• Should include the effect of temperatures (in 10°C increments above that for
accelerated testing), humidity (e.g., 75% RH or greater) where appropriate,
oxidation, and photolysis
• Should evaluate the susceptibility to hydrolysis across a wide range of pH
values when in solution or suspension
• Examining degradation products under stress conditions is useful in
establishing degradation pathways and developing and validating suitable
analytical procedures.
• Photostability testing should be an integral part of stress testing

„ Drug Product
• Photostability testing should be conducted on at least one batch
• Conditions are described in ICH Q1B.

Results from these studies will form an integral part of the information
provided to regulatory authorities

33
5 – ICH Q1A Guideline
 Section 3 - Selection of Batches

„ Drug Substance
• At least three primary batches of the drug substance.
• Batches should be manufactured to a minimum of pilot scale by the same
synthetic route as, and using a method of manufacture and procedure that
simulates the final process to be used for, production batches.

„ Drug Product
• At least three primary batches of the drug product
• The manufacturing process used for primary batches should simulate that to be
applied to production batches and should provide product of the same quality
and meeting the same specification as that intended for marketing
• Primary batches should be of the same formulation and packaged in the same
container closure system as proposed for marketing
• Two of the three batches should be at least pilot scale batches and the third
one can be smaller, if justified.
• Batches should be manufactured by using different batches of drug substance
• Stability studies should be performed on each individual strength and container
size of the drug product unless bracketing or matrixing is applied Æ ICH Q1

34
5 – ICH Q1A Guideline
 Section 4 - Container Closure System

„ Drug Substance
• Container closure system should be the same as for storage and distribution
(or should be able to simulates the packaging proposed)

„ Drug Product
• Tested dosage form should be packaged in the container closure system
proposed for marketing
– Including any secondary packaging and container label
– Studies carried out on the drug product outside its immediate container or in other
packaging materials can form a useful part of the stress testing of the dosage form or
can be considered as supporting information, respectively.

35
5 – ICH Q1A Guideline
 Section 5 - Specifications

„ Drug Substance and Drug Product

• Stability studies should include testing of attributes that are susceptible to
change during storage and are likely to influence quality, safety, and/or efficacy
• Analytical procedures should be validated and stability indicating
• References: ICH Q2, ICH Q3A/B, ICH Q6

„ Drug Product
• The testing should cover, as appropriate, the physical, chemical, biological,
and microbiological attributes, preservative content (e.g., antioxidant,
antimicrobial preservative), and functionality tests (e.g., for a dose delivery
system).
• Shelf life acceptance criteria should be derived from consideration of all
available stability information.
• It may be appropriate to have justifiable differences between the shelf life and
release acceptance criteria based on the stability evaluation and the changes
observed on storage.
• A single primary stability batch of the drug product should be tested for
antimicrobial preservative effectiveness (in addition to preservative content) at
the proposed shelf life for verification purposes, regardless of whether there is
a difference between the release and shelf life acceptance criteria for
preservative content

36
5 – ICH Q1A Guideline
 Section 5 - Specifications / “Significant change”

„ Drug Substance
• failure to meet its specification

„ Drug Product
• 5% change in assay from its initial value
• Any degradation product’s exceeding its acceptance criterion
• Failure to meet the acceptance criteria for appearance, physical attributes, and
functionality test e.g.:
– color, phase separation, resuspendibility, caking, hardness, etc
• Failure to meet the acceptance criterion for pH
• Failure to meet the acceptance criteria for dissolution for
12 dosage units

37
5 – ICH Q1A Guideline
 Section 6 - Testing frequency

„ Long term Storage condition

• Frequency should be every 3 months over the first year, every 6 months over
the second year, and annually thereafter through the proposed retest period
(For drug substances with a proposed re-test period of at least 12 months)

„ Accelerated storage condition

• a minimum of three time points, including the initial and final time points (e.g.,
0, 3, and 6 months), from a 6-month study is recommended

„ Intermediate storage condition

• When testing at the intermediate storage condition is called for as a result of
significant change at the accelerated storage condition, a minimum of four time
points, including the initial and final time points (e.g. 0, 6, 9, 12 months), from a
12-month study is recommended

„ Reduced designs, (matrixing or bracketing) where the testing frequency is

reduced or certain factor combinations are not tested at all, can be
applied, if justified Æ Q1D
Applicablefor
Applicable forDS
DSand
andDP
DP

38
5 – ICH Q1A Guideline
 Section 7 - Storage conditions

„ Storage should be evaluated under storage conditions that test thermal

stability and, if applicable, sensitivity to moisture
„ The storage conditions and the lengths of studies chosen should be
sufficient to cover storage, shipment, and subsequent use
„ The long term testing should cover a minimum of 12 months’ duration on
at least three primary batches
„ 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 outside the label storage conditions (e.g. during
shipping)
„ The general case applies if the DS / DP is not specifically covered by a
subsequent section. Alternative storage conditions can be used, if
justified.

Applicablefor
Applicable forDS
DSand
andDP
DP

39
5 – ICH Q1A Guideline
 Section 7 - Storage conditions (cont’d)

„ Drug Product
• Stability testing of the drug product after constitution or
dilution, if applicable, should be conducted to provide
information for the labeling on the preparation, storage
condition, and in-use period of the constituted or diluted
product.
• This testing should be performed on the constituted or diluted
product through the proposed in-use period on primary
batches at initial and final time points and, if full shelf life long
term data will not be available before submission, at 12
months or the last time point for which data will be available.
• Additional data accumulated during the assessment period of
the registration application should be submitted to the
authorities if requested.

40
5 – ICH Q1A Guideline
 Section 7 - Storage conditions (cont’d)

„ Drug substances - General case

Study Storage condition Minimum time period covered
by data at submission
25°C ± 2°C / 60% ± 5% r.h. or
Long term 12 months
30°C ± 2°C / 65% ± 5% r.h.
Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months

Accelerated 40°C ± 2°C / 75% ± 5% r.h. 6 months

„ Drug substances - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered
by data at submission
Long term 5°C ± 3°C 12 months
Accelerated 25°C ± 2°C / 60% ± 5% r.h. 6 months

„ Drug substances - intended for storage in Freezer

Study Storage condition Minimum time period covered
by data at submission
Long term -20°C ± 5°C 12 months

41
5 – ICH Q1A Guideline
 Section 7 - Storage conditions (cont’d)

„ Drug products - General case

Study Storage condition Minimum time period covered

by data at submission
25°C ± 2°C / 60% ± 5% r.h. or
Long term 12 months
30°C ± 2°C / 65% ± 5% r.h.
Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months
Accelerated 40°C ± 2°C / 75% ± 5% r.h. 6 months

„ Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered
by data at submission
25°C ± 2°C / 40% ± 5% r.h. or
Long term 12 months
30°C ± 2°C / 35% ± 5% r.h.
Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months
Accelerated 40°C ± 2°C / NMT 25% r.h. 6 months

42
5 – ICH Q1A Guideline
 Section 7 - Storage conditions (cont’d)

„ Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered
by data at submission
Long term 5°C ± 3°C 12 months
Accelerated 25°C ± 2°C / 60% ± 5% r.h. 6 months

„ Drug products - intended for storage in a Freezer

Study Storage condition Minimum time period covered
by data at submission
Long term -20°C ± 5°C 12 months

43
5 – ICH Q1A Guideline
 Section 8 - Stability Commitment

„ If Submission includes stability data from three production

batches covering the proposed re-test period / shelf life, a
post approval commitment is not necessary.
„ Otherwise a commitment should be made
• Study don’t cover proposed re-test period / shelf life :
– Continue through the proposed re-test period / shelf life
• Less than three production batches used:
– Enlarge studies with additional production batches, to a total of
at least three
• No production batch used:
– Commitment to place the first three production batches on
stability through the proposed re-test period / shelf life and on
accelerated studies for 6 months.

Applicablefor
Applicable forDS
DSand
andDP
DP

44
5 – ICH Q1A Guideline
 Section 9 - Evaluation

„ Determine the time at which the 95 one-sided confidence limit for

the mean curve intersects the acceptance criterion
• Calculation of re-test period (DS)
• Calculation of shelf life (DP)
„ If the batch-to-batch variability is small, it is advantageous to
combine the data into one overall estimate
„ 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 within acceptance criteria
„ Any evaluation should cover not only the assay, but also the
levels of degradation products and other appropriate attributes.
„ Reference: ICH Q1E

Applicablefor
Applicable forDS
DSand
andDP
DP

45
5 – ICH Q1A Guideline
 Section 9 – Evaluation (cont’d)
102

101

100

99
% of Declaration

98

97

96

95

Proposed shelf life or

94
Re-test period
93
0 5 10 15 20 25 30 35 40

month
46
5 – ICH Q1A Guideline
 Section 10 – Statements / Labeling

„ General
• A storage statement should be established for the labeling in
accordance with relevant national/regional requirements
• Statement should be based on the stability evaluation of the drug
substance / drug product
• Terms such as “ambient conditions” or “room temperature” should be
avoided.
„ Drug Substance
• Retest date should be displayed on the container label if appropriate.
„ Drug Product
• There should be a direct link between the label storage statement
and the demonstrated stability of the drug product.
• An expiration date should be displayed on the container label.

Applicablefor
Applicable forDS
DSand
andDP
DP

47
5 – ICH Q1A Guideline
 Submission

„ At Submission you need at least the following stability data of the

Drug product

• Based on three primary batches

• Derived from same formulation as proposed for marketing
• packaged in the same container closure system as proposed for
marketing

Condition Temp. humidity Testing data from timepoint

t=0 t=1 t=3 t=6 t=9 t=12
Long term 25°C 60% 9 9 9 9 9

Intermediate 30°C 65% 9 9 9 9

Accelerated 40°C 75% 9 9 9

48
5 – ICH Q1A Guideline
6 Other relevant ICH Guidelines

49
 Photostability Testing ► ICH Q1B ◄

„ Purpose
• Simulation of the impact of Fluorescence lamps which are used in
Hospitals
– visual Range between 400 nm and 800 nm
• Assessing the impact of near UV light which should represent
Sunlight behind a window
– UV Range 320 nm to 400 nm

„ General
• Photostability characteristics of new drug substances and products
should be evaluated to demonstrate that light exposure does not
result in unacceptable change
• Testing is carried out on a single batch of material (DS / DP)

50
6 – Other relevant ICH Guidelines
 Photostability Testing ► ICH Q1B ◄

„ Procedure
• Tests on the drug substance
• Tests on the exposed drug product outside of the immediate pack
• Tests on the drug product in the immediate pack (if necessary)
• Tests on the drug product in the marketing pack (if necessary)
„ By using
• Illumination of not less than 1.2 million lux hours
• and an integrated near ultraviolet energy of not less than 200 watt
hours/square meter
• These requirements are fulfilled by the Suntest CPS (Atlas Corp.),
which is equipped with a Xenon lamp

51
6 – Other relevant ICH Guidelines
 Stability Testing for New Dosage Forms ► ICH Q1C ◄

„ General
• A new dosage form is defined as a drug product which is a
different pharmaceutical product type, but contains the
same active substance as included in the existing drug product
approved by the regulatory authority

– immediate release tablet to modified release tablet

– oral to parenteral
– capsule to tablet
– solution to suspension

„ Procedure
• Same procedure as described in ICH Q1A(R2)
• Reduced stability database at submission time (e.g., 6 months
accelerated and 6 months long term data from ongoing studies
instead of 12 month)

52
6 – Other relevant ICH Guidelines
 Bracketing and Matrixing ► ICH Q1D ◄

„ Full Design
• A full study design is one in which samples for every combination of
all design factors are tested at all time points

„ Reduced Design
• A reduced design is one in which samples for every factor
combination are not all tested at all time points
• Before a reduced design is considered, certain assumptions should
be assessed and justified.

!!!!The
Thepotential
potentialrisk
riskshould
shouldbe
beconsidered
consideredofofestablishing
establishingaashorter
shorterretest
retest
period or shelf life than could be derived from a full design due to the
period or shelf life than could be derived from a full design due to the
reduced
reducedamount
amountofofdata
datacollected
collected!!!!

53
6 – Other relevant ICH Guidelines
 Bracketing and Matrixing ► ICH Q1D ◄

Snowball effect

Dosage
Dosage Packaging
Packaging Storage
Storage
strength
strength material
material condition
condition

0.10
0.10mg PP
PP- -Blister -20°C
mg Blister -20°C

0.25 mg Alu - Blister + 5°C

0.25 mg Alu - Blister + 5°C

Film 0.50
Film 0.50mg
mg Glas
GlasBottles
Bottles ++25°C
25°C/ /60%
60%
coated
coated
tablet
tablet 1.00
1.00mg
mg HDPE
HDPEbottles
bottles ++30°C
30°C/ /65%
65%

2.00 mg + 40°C / 75%

2.00 mg + 40°C / 75%

54
6 – Other relevant ICH Guidelines
 Bracketing and Matrixing ► ICH Q1D ◄

„ Bracketing
• 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

0.10 mg 0.25 mg 0.50 mg 1.00 mg 2.00 mg

A B C A B C A B C A B C A B C
PVC Blister 9 9 9 9 9 9

Alu Blister 9 9 9 9 9 9

Aclar Blister 9 9 9 9 9 9

HDPE Bottles 9 9 9 9 9 9

!! If the stability of the extremes is shown to be different, the intermediates are considered
!! If the stability of the extremes is shown to be different, the intermediates are considered
no more stable than the least stable extreme !!
no more stable than the least stable extreme !!

55
6 – Other relevant ICH Guidelines
 Bracketing and Matrixing ► ICH Q1D ◄

„ Matrixing

• Design of a stability schedule such that a selected subset of the total

number of possible samples for all factor combinations would be
tested at a specified time point.
• At a subsequent time point, another subset of samples for all factor
combinations would be tested.
• The design assumes that the stability of each subset of samples
tested represents the stability of all samples at a given time point

!!!!Due
Duetotothe
thereduced
reducedamount
amountofofdata datacollected,
collected,aamatrixing
matrixingdesign
designononfactors
factorsother
other
than
than time points generally has less precision in shelf life estimation and yieldsaa
time points generally has less precision in shelf life estimation and yields
shorter
shortershelf
shelflife
lifethan
thanthe
thecorresponding
correspondingfull fulldesign!!
design!!

56
6 – Other relevant ICH Guidelines
 Bracketing and Matrixing ► ICH Q1D ◄

Matrixingon
Matrixing on
TimePoints
Time Points

Matrixing
Matrixingon
on
Time Points
Time Points
and
andFactors
Factors

Key
Key

57
6 – Other relevant ICH Guidelines
 Bracketing and Matrixing ► ICH Q1D ◄

„ Matrixing is applicable, if you (have)

• good knowledge of data variability
• expect high stability of the product
• supporting data available

„ In general, a matrixing design is applicable if the supporting data

indicate predictable product stability
„ Matrixing is appropriate when the supporting data exhibit only
small variability

!!!!Requires
Requireslarge-
large-scale planning
large-scale planning(excellent
(excellentstatistical
statisticalknow
knowledges)
ledges) !!!!

58
6 – Other relevant ICH Guidelines
 Bracketing and Matrixing ► ICH Q1D ◄

Most appropriate Design

Stage Development process
Bracketing Matrixing

1 Stress Testing with drug substances --- ---

2 Stability on pre-formulation batches 9 ---

3 Stress Testing on scale-up batches 9 ---

4 Registration stability 9 ---

5 On-going stability (9) 9

6 Follow-up stability (9) 9

59
6 – Other relevant ICH Guidelines
 Evaluation of Stability Data ► ICH Q1E ◄

„ Principles of extrapolation of
7
stability data to establish a retest
period or shelf life
„ Defines when extrapolation is
applicable
6
„ Requires data from at least three
batches (DS or DP)
„ The decision tree outlines a 5
stepwise approach and offers
7 different opportunities to
calculate data 4
„ Maximum retest period / shelf
life “Y” is defined as:
Up to 2x, but not exceeding
12 months beyond the period
covered by long-term data
1 2 3
60
6 – Other relevant ICH Guidelines
 Stability Data Package for Registration Applications
in Climatic Zones III and IV ► ICH Q1F ◄

„ Covers non ICH regions

• Zone III = Hot dry (30°C/35%)
• Zone IV = Hot humid (30°C / 70%)

„ Refers to WHO Technical Report Series, No 863, Annex 5

“Stability testing of pharmaceutical products containing well established drug
substances in conventional dosage forms”

„ General case
Study Storage condition Minimum time period covered
by data at submission
Long term 30°C ± 2°C / 65% ± 5% r.h. I CH 12 months
y
Accelerated 40°C ± 2°C / 75% ± 5% r.h.
w n b 06 6 months
a 0
th dr ne 2
W i Ju
n
„ Aqueous-based drug products (packaged in semi-permeable containers)
i
Study Storage condition Minimum time period covered
by data at submission
Long term 30°C ± 2°C / 35% ± 5% r.h. 12 months
Accelerated 40°C ± 2°C NMT 25% ± 5% r.h. 6 months

„ No intermediate storage condition

61
6 – Other relevant ICH Guidelines
 ICH Zone IV discussions at WHO Meeting*

„ Calculations based on meteorological data have demonstrated

that the existing long-term stability conditions (30°C/65%RH) do
not reflect climatic conditions in many countries which have hot
and very humid areas, such as
• Brazil, Cuba, China, India and all of the
• ASEAN countries.
„ The stability of a product depends not only on the nature of the
packaging material but also on factors such as conditions during
packaging, pack design and pack geometry, including
headspace.
„ It is desirable to achieve a single harmonized, long-term stability
testing condition for Zone IV

*) STABILITY STUDIES IN A GLOBAL ENVIRONMENT, (Geneva, 13-14 December 2004)

62
6 – Other relevant ICH Guidelines
 ICH Zone IV discussions (cont’d)

„ The following options were proposed and discussed.

a) Revert 30°C / 70% r.h. as the long term condition for Zone IV
as it is likely that considerable data are already available.
This might serve a potential platform for future harmonization
between ICH and WHO

b) Change to 30°/75% r.h. as the long-term stability testing

condition for Zone IV in the interest of patient safety
worldwide

c) Add an new climatic Zone IVb to accommodate hot and very

humid areas (30°/75%). The present Zone IV (30°C/65%)
would become Zone IVa

63
6 – Other relevant ICH Guidelines
 ICH Zone IV discussions (cont’d)

„ Feedback from WHO member was quite different

• ASEAN countries prefer option b) 30°C / 75% which is also
stipulated in the “ASEAN guideline on stability study of drug
product” published in February 2005.
• ICH members prefer option a) 30°C / 70%
• IGPA (International Generic Pharmaceutical Alliance) prefers
option a) 30°C / 70%
• Amazonien countries, which represents Bolivia, Brazil,
Colombia, Cuba, Ecuador, Peru, Venezuela and Surinam
prefers option
b) 30°C / 75%, which is already their current legal
requirement.
„ Feedback from WHO members not represented at the meeting
was also requested …………….. by end of March 2005 at the
latest

64
6 – Other relevant ICH Guidelines
 ICH Zone IV discussions …. current status

„ At 40th WHO expert committee meeting (Oct. 2005) a decision

was made that the WHO stability guidelines should be amended
to reflect conditions for Zone IV as follows:

• Zone IVa: 30°C / 65% r.h.

• Zone IVb: 30°C / 75% r.h

„ It was agreed that each individual Member State within the

former Zone IV would need to indicate whether its territory
should be classified as Zone IVa or IVb

„ This process is now on-going

65
6 – Other relevant ICH Guidelines
 ICH Zone IV discussions …. consequences

„ Early stage stability studies becomes more important,

because you must clearly understand the robustness of
your product (moisture and it’s relation to temperature)
„ Maybe you must use a more protective packaging material
„ Define a globally acceptable stability protocol, like

Temp./ humidity Condition Climatic Zone Timepoint

t=0 t=1 t=3 t=6 t=9 t=12 t=18 t=24 t=36

25°C / 60% r.h Long-term I and II x - x x x x x x x

Intermediate I and II
30°C / 65% r.h. - - (x) (x) (x) (x) (x) (x) (x)
Long-term III and IV a
30°C / 75% r.h. Long-term IV b - - x x x x x x x
40°C / 75 % r.h. Accelerated I, II, II and IV - (x) x x - - - - -

50°C Stress - - (x) x - - - - - -

66
6 – Other relevant ICH Guidelines
 Validation of Analytical Methods ► ICH Q2(R1) ◄

„ The objective of validation of an analytical procedure is to

demonstrate that it is suitable for its intended purpose
„ Typical validation characteristics which should be considered and
are covered by the guideline are as follows:

„„ Accuracy
Accuracy „„ Detection
DetectionLimit
Limit(LOD)
(LOD)
„„ Precision
Precision „„ Quantitation
QuantitationLimit
Limit(LOQ)
(LOQ)
„„ Repeatability
Repeatability „„ Linearity
Linearity
„„ Intermediate
IntermediatePrecision
Precision „„ Range
Range
„„ [Reproducibility]
[Reproducibility] „„ Robustness
Robustness
„„ Specificity
Specificity

67
6 – Other relevant ICH Guidelines
 Impurities in DS / DP ► ICH Q3A/B(R) ◄

„ Listing, Reporting, Identification and Qualification of Degradation

Products

• Reporting Threshold
– A limit above (>) which a degradation product should be reported

• Identification Threshold
– A limit above (>) which a degradation product should be identified
– Achieving of the structural characterization

• Qualification Threshold
– A limit above (>) which a degradation product should be qualified
– Process of acquiring and evaluating data that establishes the biological
safety of an individual degradation product or a given degradation profile

68
6 – Other relevant ICH Guidelines
 Stability Testing of Biotechnological / Biological
Products ► Q5C ◄

„ The Guideline describes how to establish a stability program for

Biotechnological and Biological Products because of their particularly
sensitivity to environmental factors.
„ Some variations to ICH Q1A / F
• Selection of Batches contains also Intermediates
– because of their possible criticality for the final product

• Stability Indicating Profile

– Because mostly there is no single stability indicating assay
– Other type of analytical methods are applicable, e.g. electrophoresis, gel filtration,
peptide mapping

• Accelerated conditions from Q1A / F are not appropriate for

Biotechnological/Bilological products, so the conditions should be selected on
a case-by-case basis

• Testing frequency varies depending on the shelf-life

– Shelf life < 1 year: t = 0, 1, 2, 3, 6, 9, 12
– Shelf life > 1 year: t = 0, 3, 6, 9, 12, 18, 24, 36, 48, 50 (same as Q1A)

69
6 – Other relevant ICH Guidelines
7 Requirements for performing Stability studies

70
 Instrumentation

„ Storage capacities
• Stability chambers
• Stability cabinets
• Refrigerators
• Freezers
„ Monitoring and Alert System
„ Back-up capacities
„ Supporting environment
• Database for tracking of pull-dates
• Ensure full traceability of samples
• SOPs
– Labeling and Storage of Samples
– Handling of Stability studies
– (Re)-Qualification of systems
– Deviations
– Access to storage area

71
7 – Requirements for performing Stability studies
 Equipment Qualification

„ Initial Qualification
• Empty unit
• Simulated regular use (e.g. filled with packaging materials)
• Simulated breakdown (e.g. power failure, water failure)
• Qualify Climatic condition (Requirements acc. to ICH Q1A)
– Stability of conditions over a predefined time period (e.g. 24 hours)
– Temperature and Humidity Mapping (e.g. 15 points)
• Qualify Monitoring and Alert System
– Computerized System?
» 21CFR11 compliance

„ Periodic Requalification / Calibration

• Requalification period: e.g. 12 month
• Temperature / humidity mapping (e.g. 2 hours)

72
7 – Requirements for performing Stability studies
 Guidelines

„ Study Design & Storage conditions

• ICH Q1 Guidelines
– Storage duration & conditions
– Stability design (Bracketing / Matrixing)
– Evaluation of data
– Photostability testing
• ICH Q5C
– Stability Testing of Biotechnological / Biological products
• In Asia: Asean Guideline on Stability study of drug product
„ Method Development & Validation (Revalidation)
• ICH Q2 Guidelines
• EMEA Guidelines
„ Transfer of Analytical Methods
• No guidelines available

73
7 – Requirements for performing Stability studies
….. and how do you test for stability?

74
Thank
Thankyou
youfor
foryour
yourattention
attention

Any
Anyquestions?
questions?

Your
Yourcontact
contactin
inIndia
India
SGS
SGSIndia
India
Dr.
Dr.Meenakumari
Meenakumari
Ticel
TicelBiotech
BiotechPark
Park
Taramani
Taramani Road,Taramani
Road, Taramani
Chennai 600 113
Chennai 600 113

 customercare.lssindia@sgs.com
 customercare.lssindia@sgs.com
www.sgs.com
www.sgs.com

75