Stability

Global Module 3
Module 3.2.P.8: Stability
Andrew Willis
Contact: agwillis1@btinternet.com
Telephone: +(0)7415888639
2011
Contents
y
Introduction to 3.2.P.8
Structure
Considerations on different dosage forms
Climatic zones
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Presentation title (edit in View > Header and Footer)
Module 3.2.P.8: Introduction

y
y
Provides an overview of the stability data

Applicant must show that stability data supports the
proposed end of shelf life product specification and as
such are:
Of an appropriate standard
Address key stability parameters
Suitable for the designated purpose
Meets guidance (e.g manufacturing process, batch size, packaging)
Consider bulk packaging
Month 00, 0000
Module 3.2.P.8: Structure

y
3.2.P.8.1: Stability Summary and Conclusions

State shelf life
Confirms trends over predicted shelf-life
Demonstrates compliance to guidelines
3.2.P.8.2: Post-approval Stability
3.2.P.8.3: Data
Pivotal data
Supporting data
y
Month 00, 0000
Module 3.2.P.8.1
y

Discussion of pivotal stability
x Information on batches studied (at least 3
batches)
x Test methodology
x Stability indicating tests
x Summary of stability protocol
General Case
Long term: 25C/60% RH or 30C/65% RH
Intermediate: 30C/65% RH
Accelerated: 40C/75% RH
Month 00, 0000
Example Stability Protocol Summary
Month 00, 0000
Module 3.2.P.8.1
y

x Information on batches studied
x Protocol/test methodology
Discussion of other studies
x Shipping studies
x Freezethaw studies
x Forced degradation studies
x Photostability
All the above studies should be included unless
justified
Month 00, 0000
Module 3.2.P.8.1
y

continued
Discussion of other studies
In-use stability (if applicable)
Short summary of results
x Comment on extrapolations (if applicable)
Statement of shelf-life and proposed storage

condition
Month 00, 0000
Extrapolating Stability Data
Month 00, 0000
Module 3.2.P.8.2
y
3.2.P.8.2: Post-approval Stability

Commitment to continue study to conclusion
x Meets all Climate Zone Requirements
x End of Shelf-life Test period
Describe any other ongoing stability commitments

x Always include maintenance
Complies with guidance

x As detailed in P2 - section
Month 00, 0000
10
Module 3.2.P.8.3
y
3.2.P.8.3: Data
All data in tabular format (preferable to have all
results in numerical format not conforms)
Discussion of results, including any statistical analysis
Discussion of tests and any method validation
Presentation style - clear, legible, tabulated
Trends easily observed
Month 00, 0000
11
Stability Considerations on
Dosage Form
y
Data requirements on different dosage forms

Oral solid
Oral liquid
Creams/foams
Inhalations
Sterile
Consider primary packaging and delivery system
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12
Climatic Zones
y
Consider where product is to be marketed and any

regional stability testing guidelines
y
y
Climatic Zones I & II EU, US & Australia

III & IV Africa & India
In general most application made for climatic zones I

and II
ICH 30C/65%RH can be considered long term for
climatic zones III and IV
Some countries will accept 30C/75%RH
Led to the withdrawal of ICH Q1F
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13
Regulatory
Guidelines
Governing Stability
Testing Operations
Month 00, 0000
14
Regulatory Guidelines Governing

Stability Testing Operations
y
Identification of ICH Guidelines
Regulatory guidelines governing stability studies are ICH

Guidelines.
ICH stands for International Conference on

Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human use.
The main objectives of ICH is the harmonization of

registration applications within the three regions of the
EU, Japan and the United States.
Month 00, 0000
15

y
ICH Steering Committee: Six parties directly involved in the decision 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

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16
Regulatory Guidelines
Governing Stability Testing
Operations
y
Official Observers: Canada, WHO (World Health

Organisation), EFTA (Europe Free Trade Area)
Interested Parties: Pharmacopoeia, IGPA, WSMI
Meetings are rotated among US, EU and Japan
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17

y
A Brief History of ICH
1980s
Harmonisation 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 harmonisation.
1989
At the WHO Conference of Drug Regulatory Authorities (ICDRA), in Paris, specific

plans for action began to materialise.
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.
Month 00, 0000
18

y
ICH Guidelines are divided per Theme:
Quality Guidelines Q (Chemical and pharmaceutical Quality), with the parent

Guideline ICHQ1A
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.
Multi-disciplinary Guidelines M, covering Medical Terminology, Electronic Standards

for Transmission of Regulatory Information etc. Once of the most important is:
Guideline M4 on The Common Technical Document (CTD)
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Regulatory Guidelines Governing Stability

Testing Operations
y
ICH Q1- Stability Guidelines
Photostability Testing of New Drug Substances and Products (Q1B)
Stability Testing for New Dosage Forms (Q1C)
Bracketing and Matrixing Designs for Stability Testing of New Drug Substances
and Products (Q1D)
Evaluation of Stability Data (Q1E)
Stability Data Package for registration Applications in Climatic Zones III and IV
(Q1F Withdrawn)
Stability Testing of New Drug Substances and Products (Q1A(R2))
IH
ASEAN
Stability Testing for Biotechnological/Biological Products (Q5C)

Month 00, 0000
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10

Representation of ICH Guidelines
Month 00, 0000
21
Regulatory Guidelines Governing Stability

Testing Operations
y
Comprehensive review of ICH Q1A, revised Guideline
Objective of ICH Q1A (R2) Guideline is to define common principles of stability

testing for both Drug Substances and Drug Products.
ICH Q1A (R2) addresses the information to be submitted in registration

applications for new molecular entities and Associated drug products.
ICH Q1A (R2) is dedicated to climatic Zone I and II
ICH Q1A (R2) does not currently seek to cover the information to be submitted
for
Abbreviated or abridged applications
Variations
Clinical trial applications
Month 00, 0000
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11

y

(contd)
The structure of ICH Q1A (R2) is as follows:
1. General
2. Stress testing
3. Selection of batches
4. Container closure system
5. Specification
6. Testing frequency
7. Storage conditions
8. Stability commitment
9. Evaluation
10. Statements/Labelling
Month 00, 0000
23

y
Comprehensive review of ICH Q1A, revised

Guideline (contd)
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 behaviour
and
properties of the drug substance and from

stability studies on the drug substance and on
experience gained from clinical formulation studies
Month 00, 0000
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12

yComprehensive
(contd)
y2
review of ICH Q1A, revised Guideline
- Stress Testing - Drug Substance
Carried
out on a single batch
Should
include the effect of temperatures (in 10C 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 (conditions are

described in ICH Q1B)
Month 00, 0000
25

y

(contd)
2 - Stress Testing - Drug Product
Photostability testing should be conducted on at least one batch
Conditions are described in ICH Q1B
Results from these studies (on drug substance and drug product) will form an
integral part of the information provided to regulatory authorities.
Month 00, 0000
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13

y

(contd)
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
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y

(contd)
3 - Selection of 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
Month 00, 0000
14

y Comprehensive
(contd)
y
3 - Selection of Batches - Drug Product (contd)
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 Q1D)
Month 00, 0000

y

(contd)
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
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Footer)
15

y

(contd)
5 - Specifications of Drug Substance

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 indicated.
References to other ICH Guidelines: ICH Q2, ICH Q3A/B, ICH Q6.
Month 00, 0000

Footer)

y

(contd)
5 - Specifications of 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.
Month 00, 0000

Footer)
16

y
Comprehensive review of ICH Q1A, revised

Guideline (contd)
5 - Specifications of Drug Product (contd)
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 forpreservative
content.
Month 00, 0000

y Comprehensive
(contd)
y
5 - Specifications of Drug Product and Drug Substance: Significant

change
Drug Substance
Failure to meet its specification
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17

y Comprehensive
(contd)
5 - Specifications of Drug Product and Drug Substance: Significant change
Drug Product
- 5% change in assay from its initial value
- Any degradation product exceeding its acceptance criterion
- Failure to meet the acceptance criteria for appearance, physical attributes and
functionality test, e.g. colour, phase separation, re-suspendibility, caking, hardness, etc.
- Failure to meet the acceptance criterion for pH
- Failure to meet the acceptance criteria for dissolution for 12 dosage units
(contd)
Month 00, 0000

y

(contd)
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 re-test period
(for drug substances and drug product).
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.
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18

y Comprehensive
(contd)
6 - Testing Frequency (contd)
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.
Month 00, 0000

y

(contd)
6 - Testing Frequency (contd)
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 (to be developed further)
y
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19

y

(contd)
7 - Storage Conditions
Storage should be evaluated under storage conditions that test thermal stability and, if
applicable, sensitivity to moisture.
y
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

y
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).
Month 00, 0000

y

(contd)
7 - Storage Conditions (contd)
Stability testing of the drug product after constitution or dilution, if applicable, should be
conducted to provide information for the labelling 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.
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20

y

(contd)
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:
If the study does not cover the proposed re-test period/shelf life: continue
through the proposed re-test period/shelf life
Fewer than three production batches used: enlarge studies with additional
production batches, to a total of at least three batches
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.
Month 00, 0000

y
Comprehensive review of ICH Q1A, revised Guideline (cont
9 - Evaluation
Defined in ICH Q1E (developed further)
Month 00, 0000
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21

y Comprehensive
(contd)
10 Statements/Labelling
General
- A storage statement should be established for the labelling in accordance with relevant
national/regional requirement
- 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.
Month 00, 0000

y Comprehensive
(contd)
y
10 Statements/Labelling
Drug Substance
Re-test 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.
Month 00, 0000
22

y Comprehensive
(contd)
y
Submission
At time of submission you need at least the following stability data on the
Drug product:
Based on three primary batches, manufactured according to GMP
Derived from same formulation as proposed for marketing
- Packaged in the same container closure system as proposed for marketing
Month 00, 0000

Stability Testing Operations (Other
ICH Guidelines (Q1C))
y
Stability Testing for New Dosage Forms defined in ICH Q1C
General
A new dosage form is defined as a drug product that 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 months) may be acceptable
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Questions
Any Questions?
Month 00, 0000
47
24

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Global Module 3

Module 3.2.P.8: Stability

Considerations on different dosage forms

Month 00, 0000

Presentation title (edit in View > Header and Footer)

Module 3.2.P.8: Introduction

Provides an overview of the stability data

Month 00, 0000

Presentation title (edit in View > Header and Footer)

Module 3.2.P.8: Structure

3.2.P.8.1: Stability Summary and Conclusions

3.2.P.8.2: Post-approval Stability

Presentation title (edit in View > Header and Footer)

3.2.P.8.1: Stability Summary and Conclusions

Presentation title (edit in View > Header and Footer)

Example Stability Protocol Summary

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Presentation title (edit in View > Header and Footer)

3.2.P.8.1: Stability Summary and Conclusions

Presentation title (edit in View > Header and Footer)

3.2.P.8.1: Stability Summary and Conclusions

Statement of shelf-life and proposed storage

Presentation title (edit in View > Header and Footer)

Extrapolating Stability Data

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Presentation title (edit in View > Header and Footer)

3.2.P.8.2: Post-approval Stability

Describe any other ongoing stability commitments

Complies with guidance

Month 00, 0000

Presentation title (edit in View > Header and Footer)

Presentation style - clear, legible, tabulated

Trends easily observed

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Presentation title (edit in View > Header and Footer)

Data requirements on different dosage forms

Month 00, 0000

Presentation title (edit in View > Header and Footer)

Consider where product is to be marketed and any

Climatic Zones I & II EU, US & Australia

In general most application made for climatic zones I

Presentation title (edit in View > Header and Footer)

Presentation title (edit in View > Header and Footer)

Regulatory Guidelines Governing

Identification of ICH Guidelines

Regulatory guidelines governing stability studies are ICH

ICH stands for International Conference on

The main objectives of ICH is the harmonization of

Presentation title (edit in View > Header and Footer)

Regulatory Guidelines Governing

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

Presentation title (edit in View > Header and Footer)

Official Observers: Canada, WHO (World Health

Interested Parties: Pharmacopoeia, IGPA, WSMI

Meetings are rotated among US, EU and Japan

Month 00, 0000

Presentation title (edit in View > Header and Footer)

Regulatory Guidelines Governing

A Brief History of ICH