Stability Studies India 0307

Performing Stability studiesPerforming Stability studies

Ulrich MarkensHead of QC Testing Labs AsiaSGS Life Science Services

Hyderabad, Mumbai, Ahmedabad - INDIAMarch 24th, 26th, and 28th 2007

2

FDA Warning Letter Report 2006

2005 2006 ∆

Drugs (part 211)

17 20 18%

Blood, Blood products, Biologicals(part 600 606, 610, 630, 640, 680)

9 10 11%

Medical devices (part 820)

107 79 -26%

3

FDA Warning Letter Report 2006 (cont’d)

Top 5 findingsTop 5 findings

4

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

5

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)

1 - General Information

6

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 acceptablechanges of the drug substance or drug product


7

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


8

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

6. Follow-up StabilitiesScope

• Solubility Profile• Hygroscopicity• Thermal stability

(Melting point, Polymorphism)• Chemical stability

1 BatchUp to 3 month Ad 1Ad 1

Selection of samples• API, excipient, batches

Scope• Appearance• Appropriate physical-chemical parameter• Assay / Degradation products

Up to 3 month Ad 2Ad 2

Scope• Determination of expire date • Determination of preliminary specifications• Release of clinical batches• Monitoring of samples during the clinical phases• Definition of storage conditions• Definition of Tests for registration stability

Up to 36 month Ad 3Ad 3


9

2 Examples for Stability testing designs

10

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)

2 - Examples for Stability testing design

11

Examples for stability testing designs (cont’d)

Testing scope for TABLETS

• Physical-chemical properties– Appearance– Mean mass– Water content– Hardness– Disintegration– Dissolution


• Microbial properties– Microbial purity

• Container closure system properties– Functionality tests (e.g. extraction from blister)


12


Testing scope for CAPSULES

• Physical-chemical properties– Elasticity– Mean mass– Mean filling mass– Water content (Capsule and content)– Disintegration– Dissolution



• Container closure system properties– Functionality tests (e.g. extraction from blister)


13


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


• Container closure system properties– Functionality tests


14


Testing scope for LIQUID FORMS for inj. and PARENTERALIA

• Physical-chemical properties– pH– Loss on weight– Color & clarity of solution





15


Testing scope for SEMI LIQUID FORMS

• Physical-chemical properties– Appearance, odor, homogeneity, consistency– Loss on weight– Viscosity– Content uniformity (within the container)





16

3 Climatic Zones

17

Climatic Zones / Storage conditions

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

3 – Climatic Zones

Climatic ZoneCountries Temp. MKT humidity Temp. humidity

°C °C % r.h. °C % r.h.

Climatic Zone I "Temperate"

Japan, United Kingdom, Northern Europe, Canada, Russia, United States

Climatic Zone II"Mediterranean, Subtropical"

Japan, United States, Southern Europe

Climatic Zone III "Hot, dry"

Iran, Iraq, Sudan

Climatic Zone IV"Hot, humid"

Brazil, Ghana, Indonesia, Nicaragua, Philippines

7627,426,7

30 35

7030

21,6

26,4 27,9 35

60255222

Calculated data Derived data

20 20 42 21 45

18

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


19

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 ….


20


2 Examples for Stability testing design

3 Climatic Zones


5 ICH Q1A Guideline



21

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

4 – ICH and Guidelines overview

22

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 withnon-ICH countries and regions

• WHO• The European Free Trade Area (EFTA),

represented by Swissmedic Switzerland • Health Canada


23

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


24

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)


25

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)


26

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

Products; June 1998– One fits all document– Considers ICH Q1A, Q1B, Q1C and Q5CWithdrawn by FDA

In June 2006

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


27

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.


28

FDAFDAFDA

ASEANASEANASEAN

WHOWHOWHO

Guidelines

ICH Q1AICH Q1AICH Q1A

ICHQ1B

ICHICHQ1BQ1B

ICH

Q1CICH

ICH

Q1CQ1C

ICH

Q1DIC

HIC

HQ

1DQ

1DICHQ1F

ICHICHQ1FQ1F

ICHQ1E

ICHICHQ

1EQ

1E

ICHQ2

ICHICHQ2Q2

ICHQ5

ICHICHQ5Q5

Stability Testing of New DS and DP (Climatic Zone I and II)

Photostability Testing

Bracketing and Matrixing

New Dosage FormsEvaluation of Stability Data

Stability Testing in Climatic Zones III and IV

Analytical Validation

Biotechnological Products

ICHQ3A/B/C

ICHICHQ3A/B/CQ3A/B/C ICH

Q6A/BICHICH

Q6A/BQ6A/BImpurities

Specifications


29

5 ICH Q1A Guideline

30

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

5 – ICH Q1A Guideline

31

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


32

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


33

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


34

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 ICH Q1


35

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.


36

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


37

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


38

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 Q1D

Applicable for DS and DPApplicable for DS and DP


39

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.



40

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.


41


Drug substances - General case

Drug substances - intended for storage in a Refrigerator

Drug substances - intended for storage in Freezer


Study Storage condition Minimum time period covered by data at submission

Long term 25°C ± 2°C / 60% ± 5% r.h. or30°C ± 2°C / 65% ± 5% r.h. 12 months

Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months

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


Long term 5°C ± 3°C 12 months



Long term -20°C ± 5°C 12 months

42


Drug products - General case

Drug products - packaged in Semi-permeable containers









Accelerated 40°C ± 2°C / NMT 25% r.h. 6 months

43


Drug products - intended for storage in a Refrigerator

Drug products - intended for storage in a Freezer



Long term 5°C ± 3°C 12 months



Long term -20°C ± 5°C 12 months

44

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.



45

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, theoverall 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



46

Section 9 – Evaluation (cont’d)

93

94

95

96

97

98

99

100

101

102

0 5 10 15 20 25 30 35 40

month

% o

f Dec

lara

tion

Proposed shelf life orRe-test period


47

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.



48

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. humidityt=0 t=1 t=3 t=6 t=9 t=12

Long term 25°C 60%

Intermediate 30°C 65%

Accelerated 40°C 75%

Testing data from timepoint

49


50

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)

6 – Other relevant ICH Guidelines

51

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


52

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)


53

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 potential risk should be considered of establishing a shorter retest period or shelf life than could be derived from a full design due to the

reduced amount of data collected !!

!! !! The potential risk should be considered of establishing a shorter retest period or shelf life than could be derived from a full design due to the

reduced amount of data collected !!


54


0.10 mg0.10 mg

0.25 mg0.25 mg

0.50 mg0.50 mg

1.00 mg1.00 mg

2.00 mg2.00 mg

PP - BlisterPP - Blister

Alu - BlisterAlu - Blister

Glas BottlesGlas Bottles

HDPE bottlesHDPE bottles

-20°C-20°C

+ 5°C+ 5°C

+ 25°C / 60%+ 25°C / 60%

+ 30°C / 65%+ 30°C / 65%

+ 40°C / 75%+ 40°C / 75%

Film coated tablet

Film Film coated coated tablettablet

Dosage strengthDosage Dosage strengthstrength

Packaging material

Packaging Packaging materialmaterial

Storage conditionStorage Storage

conditioncondition

Snowball effect


55


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

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

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


A B C A B C A B C A B C A B C

PVC Blister

Alu Blister

Aclar Blister

HDPE Bottles

0.10 mg 0.25 mg 0.50 mg 1.00 mg 2.00 mg

56


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 to the reduced amount of data collected, a matrixing design on factors otherthan time points generally has less precision in shelf life estimation and yields a

shorter shelf life than the corresponding full design!!

!! !! Due to the reduced amount of data collected, a matrixing design on factors otherthan time points generally has less precision in shelf life estimation and yields a

shorter shelf life than the corresponding full design!!


57


Matrixing on Time Pointsand Factors

Matrixing on Time Pointsand Factors

Matrixing on Time PointsMatrixing on Time Points

KeyKey


58


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 large-scale planning (excellent statistical know ledges) !!!! Requires large!! Requires large--scale planning (excellent statistical know ledges) scale planning (excellent statistical know ledges) !!


59



Bracketing Matrixing

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

2 Stability on pre-formulation batches ---

3 Stress Testing on scale-up batches ---

4 Registration stability ---

5 On-going stability ( )

6 Follow-up stability ( )

Most appropriate DesignDevelopment processStage

60

Evaluation of Stability Data ► ICH Q1E ◄

7

6

5

4

321

Principles of extrapolation of stability data to establish a retest period or shelf life

Defines when extrapolation is applicable

Requires data from at least three batches (DS or DP)

The decision tree outlines a stepwise approach and offers 7 different opportunities to calculate data

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


61

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

Aqueous-based drug products (packaged in semi-permeable containers)

No intermediate storage condition



Long term 30°C ± 2°C / 65% ± 5% r.h. 12 months



Long term 30°C ± 2°C / 35% ± 5% r.h. 12 months

Accelerated 40°C ± 2°C NMT 25% ± 5% r.h. 6 months

Withdrawn by ICH

in June 2006

62

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 hotand 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 thepackaging material but also on factors such as conditions duringpackaging, 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)


63

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


64

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


65

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


66

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 Zonet=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

30°C / 65% r.h. Intermediate Long-term

I and II III and IV a

- - (x) (x) (x) (x) (x) (x) (x)

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 - - - - - -

Timepoint

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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:

AccuracyPrecision

RepeatabilityIntermediate Precision[Reproducibility]

Specificity

AccuracyPrecision

RepeatabilityIntermediate Precision[Reproducibility]

Specificity

Detection Limit (LOD)Quantitation Limit (LOQ)LinearityRangeRobustness

Detection Limit (LOD)Quantitation Limit (LOQ)LinearityRangeRobustness


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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


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Stability Testing of Biotechnological / Biological Products ► Q5C ◄

The Guideline describes how to establish a stability program forBiotechnological 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)


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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

7 – Requirements for performing Stability studies

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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)


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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


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….. and how do you test for stability?

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Your contact in India

SGS IndiaDr. MeenakumariTicel Biotech ParkTaramani Road, TaramaniChennai 600 113

[email protected]

www.sgs.com

Your contact in India

SGS IndiaDr. MeenakumariTicel Biotech ParkTaramani Road, TaramaniChennai 600 113

[email protected]

www.sgs.com

Thank you for your attention

Any questions?

Thank you for your attention

Any questions?

Documents

Stability Studies India 0307