Stability Studies ?

PRESENTATION ON ICH TOPICS &
GUIDELINES WITH A SPECIAL REFERENCE TO
STABILITY STUDIES
From
Devesh Kumar Singh
Sr. General Manager
Intas Pharmaceuticals Lt.d Sikkim
The presentation will be in Five parts:
• Part-I : Quality topics-Stability

Guidelines(Q1A).
• Part-II : Photo Stability (Q1B).
• Part-III : Evaluation for Stability Data
(Q1E).
• Part-IV : Reduced Design – Bracketing &
matrixing (Q1D).
• Part-V : SUPAC Guidance
Stability Studies – an overview
The Five ICH Steps
◼ Step 1: Technical Discussion in EWG
(Expert Working Group).
◼ Step 2: Consensus achieved.
◼ Step 3: Formal Consultation.
◼ Step 4: Finalised Text/Sign off.
◼ Step 5: Implementation in 3 regions
(USA, European Country & Japan).
Guidelines for Stability Testing:
• ICH guidelines on Stability testing of new drug
substances and drug products
• USFDA guidelines on Stability testing
• CPMP guidelines on stability
• WHO guidelines on stability testing of pharmaceutical products
Abbreviations – commonly used
• ICH: International Committee for harmonisation
• CPMP: Committee for proprietary Medicinal Products
• EMEA: European Agency for the evaluation of Medicinal products
• EFPIA: European Federation of Pharmaceutical Industries & associations
• FDA: Food and Drug Administration
• PhRMA: Pharmaceutical Research and Manufacturers of America
• MHLW: Ministry of Health, Labour Welfare
• JPMA: Japan Pharmaceutical Manufacturers Association
Stability Studies
◼ The ability of a Pharmaceutical product to retain its
properties within the limits throughout its shelf life.
◼ Aspects of Stability, that are to be considered include :

Physical, Chemical, Microbiological & Bio-Pharmaceuticals.
Objective
◼ To provide evidence on how the quality

of a Drug Substance/ Drug Product
varies with the time under influence of
variety of environmental factors such as
Temperature, Humidity & Light.
Why Stability Studies are required:-
◼ To recommend retest period
◼ To assign shelf life
◼ To recommend the storage conditions
◼ To review the product quality
◼ To fulfill the regulatory requirement for dossier
submission.
◼ Why the stability testing is an important issue ?

◼ In order to demonstrate that:
- the clinical effect
- the patient safety
- the quality
- of the drug is maintained during its maximal
time of storage and intended use.
Starting a Study
Contents of a stability protocol
Setting the 'start date' for a stability study
Determining the 'due dates' for a stability study protocol
The initial certificate of analysis at to for a stability study
SOP Control
Format and layout of standard operating procedures
Indexing procedure for stability studies
Index for stability sops
Study Parameters
Setting limits for check specifications in a stability study.
Number and size of batches for stability testing.
Sampling
Number of samples required for performing stability tests
Labeling of stability study samples
Storage configuration of samples in a stability environment
Storing the stability study samples under controlled conditions prior to
analysis
Study Conditions
Intervals and climatic conditions for a development stability study
Intervals and climatic conditions for a pivotal/bioequivalence
stability study
Intervals and climatic conditions for a validation/pm stability study
Placing the reference listed drug (RLD) on stability
Packaging procedures
Sampling and testing of pivotal batches - tablet & capsule dosage forms.
Sampling and testing of pivotal batches - powder & syrups for
reconstitution.
Container systems
Container-liner-closure systems for a stability study.
Certification of a container-liner-closure system.
Test methods
The control of analytical methods #'s and edition #'s in stability
documentation
Test results
Reporting test results of a stability study.
Procedures for handling abnormal or OOS results in a stability
study.
Audit and Review Raw Data
Auditing stability data in laboratory notebooks
Cross-referencing laboratory notebooks with computerized stability
documentation
Chart Control
Recording stability study climatic conditions
Review and control of temperature and humidity recording charts
Validation and Sanitation
Periodic revalidation of climatic rooms and chambers
Sanitation and housekeeping requirements of climatic chambers
Corrective Action
Fault correcting procedures (after breakdowns) during a Stability Study
Emergency procedures during a stability study
Stopping a Study
Conditions for stopping a stability study.
Self Inspection
Self inspection procedures in a stability department.
Job Description and Training
Job description of stability department personnel
Using stability SOPs and compliance program as stability training tools.
The Do's and Don'ts of a stability study - a department training tool.
Stability department compliance staff training
Reviewing Documentation
Review and auditing stability study documentation.
The layout and format of a regulatory stability report (a filed report)
Documentation requirements for a stability study - contents
of a stability dossier
Closing a Study
Accepting and signing-off a completed stability study.
International stability Guidelines
Country Guideline Year of
introduction
Japan Stds for Stability Testing of new Drugs 1980 & 1984 ®
UK Guidance notes on Applications for product 1984

licenses
Zimbabwe Guidelines for the stability testing 1985
Ethiopia Requirements of the registration of drugs 1986

for human use
USA Submitting documentation for the stability 1987
of Human Drugs & biologics
European union Stability testing on Active ingredients & 1988
Finished products
Global climatic zones:
4 segments based on environmental conditions

Classification according to four
Climatic Zones
Designation Temperature Yearly Avg of

(MKT C) RH %
I Moderate 21°C 45%
II Subtropical or 25°C 60%

Mediterenean
III Hot & Dry 30°C 35%
IV Hot & 30°C 70%

Humidity
Distribution of Nation into
different Climatic Zones :-
Regions Zones I & II Zones III & IV
European & Uk All Countries -
American Chile, Canada Brazil,Jamaica,

United States Venezuela
Asian China,Japan, India,Philippines,Sri
Turkey Lanka
African South Botswana, Ghana,

Africa,Zambia,Zimbabwe Uganda
Australian/Ocean Australia,New Zealand Fiji, Papua,New-Guinea

ICH Drug Stability Guidelines
Code Guideline Finalised Ad opted By
ICH CPMP MHLW USFDA
Q1A(R2) Stability testing of new FEB-2003 Mar-2003 June-2003 Nov-2003

drug Substances &
Products
Q1B Photostability testing of Nov-1996 Dec-1996 May-1997 May-1997
new Drug
Substances/Products
Q1C Stability testing of new Nov-1996 Dec-1996 May-1997 May-1997
dosage forms
Q1D Bracketing & matrixing Feb-2002 Feb-2002 July-2002 Jan-2003
Designs for stability
testing of new drug
substances/ Products
Q1E Evalution of Stability Feb-2003 Mar-2003 June-2003 June-2004
Data
Q5C Stability testing of Nov-1995 Dec-1995 Jan-1998 July-1996
Biotechnological/biolog
ical products
Q1F Stability testing of Withdrawal - - -
Biotechnological/biolog -June-2006
ical products
PROGRESSIVE CHANGES IN ICH GUIDELINE
Q1A Q1A(R) Q1A(R2)

Testing Frequency
0, 3, 6, 9, 12,18, 0, 3, 6, 9, 12,18, 0, 3, 6, 9, 12,18,
Long Term 24, … .months 24, … .months
24, … .months
0, 3, 6, 9 & 12 0, 3, 6, 9 & 12 0, 3, 6, 9 & 12

Intermediate months months months
0, 1, 2, 3 & 6 0, 3 & 6 0, 3 & 6

Accelerated months months months
CHANGE
5 point study to 3 point study

Q1A Q1A(R) Q1A(R2)

Stability Storage
Condition 25  20C/ 60  5% RH
25  20C / 25  20C / or 30  20C/65  5% RH
Long Term
60  5% RH 60  5% RH (Decision is left to
the applicant)
CHANGE
30  20C / 30  20C / 30  20C /

Intermediate 60  5% RH 60  5% RH 65  5% RH
CHANGE
40  20C / 40  20C / 40  20C /

Accelerated 75  5% RH 75  5% RH 75  5% RH
Q1A Q1A(R) Q1A(R2)

Body of the Body of the
Stress Testing Glossary guideline guideline
CHANGE
Post Approval Clarity provided Clarity provided

Commitment Ambiguous
for the commitment for the commitment
CHANGE
Specification
Testing No cross
Cross reference Cross reference
reference
Procedure available
*Q6A & Q6B *Q6A & Q6B
Acceptance No cross
Cross reference Cross reference
Criteria reference
available
*Q6A & Q6B *Q6A & Q6B
* : Q6A & Q6B refers to specifications, test procedures & acceptance criteria
•Stages of stability :
- Pre-formulation / pre-experimental stability.
- Formulation / experimental stability
- Pilot / post experimental stability
- Production / commercial stability
Stability studies during product life-cycle
Submission
Development and Approval
Post-approval
• Stress testing •Formal •Follow-up

• Commitmen
• Photostability studies stability
t batches
• Studies to support for the program
application
process & product •Stability
development studies initiated
•Clinical trial stability by:
• Shipping and - Changes
In-use stability - Deviations
•Intermediates
Stress Testing for Drug
Substances & Product:-
To be carried out on a single batch of the drug
A. General:- The Design of the stability
◼
substances.
◼ It can help to identify the likely degradation
products which can help to establish:- program for the finished product should
◼ i. The degradation path way. be based on the knowledge of the
Ii. The intrinsic stability of the molecule.
◼
behaviour & properties of the drug
◼ Iii. Valdate the stability indicating power of the
analytical procedures used. substances & the experience gained
◼ Photo stability testing should be an integral part from clinical formulation studies & from
of stress testing. the stability studies on the drug
substances.
◼ Classification of API according to stability :-
◼ Category Sum of
Degradatio
Products:-
1. Very Stable(s) <LOQ*
2. Stable (s) LOQ*-1.5%
3. Unstable (I) 1.5%-10.0%
4. Very Unstable (I) >10%
◼ Batches to be tested:
Guide Applicability Min. no. Size & type
line of batch
ICH New drug substances 3 Pilot scale
New drug products 3 2 pilot scale, 1
smaller
WHO Products containing easily degradable 3 Pilot o full scale
actives production
Products containing established and 2 Different production
stable substances batches
• Ongoing stability No.of batches W H O requirement
• One batch per year
• One batch alternate year (for stable products)
• One batch every 3 – 5 years (if stability profile is available)
USFDA Bulk drug substances 1 Pilot scale
Simple dosage forms 1 Pilot scale
Others, including complex dosage 3 2 pilot scale, 1
forms and drug products without smaller
significant body of information
CPMP Existing active substances 2 or 3 Production scale
Conventional dosage forms containing 2 Pilot scale
stable actives
Critical dosage forms (prolonged 3 2 pilot scale, 1
release forms) or when active smaller
substances are known to be unstable
Container Closure System :
◼ Stability study should be conducted on
the drug substances/ product packed in
a container closure system as that
proposed for storage & distribution.
Incase of drug product should be
performed for individual strengh &
pack.
Specifications :
➢ List of tests.
➢ Testing procedure.
➢ Acceptance criteria (at the time of release / shelf life).
➢ Reference standards.
➢ In-process tests.
➢ Physical tests such as particle size distribution
➢ Parametric releases.
➢ Various decision trees
➢ Impurities
➢ Micro limits.
The testing should cover as appropriate : chemical, physical,

biological & microbiological parameters. Validated analytical
method should be adopted.
• Stability Specification
Product relase
End shelf life ( Stability)
specifications:
specification
”…include those attributes
The likely changes on
of the drug product/drug
storage and the rationale for
substance that are
the selection of attributes to
susceptible to change
be tested in the formal
during storage and likely to
stability studies should be
influence quality, safety
stated”
and/or efficacy”
Testing Frequency :-
◼ 1. Long Term :- First Year – Every 3 months
2nd Year – Every 6 months
Thereafter : Annually as per
the assigned shelf life.)
◼ 2. Accelerated term(0,1,2,3 & 6 months-generaly
accepted frequency)
◼ 3. Accelerated fallback or Intermediate :-
(0,1,2,3,6 & 12 months-generaly accepted
frequency)
Testing frequency and storage conditions
Yearly
thereafter
Data at submission
Long Term Mdr.

(25°C/60%RH) 0 3
6 9 12 18 24 36
Duration: Minimum
Accelerated Mdr. full shelf-life
(40°C/75%RH) 0 3
6
Accelerated Mdr.
if significant 0 3 6
change is expected Extra testing
(40°C/75%RH) Optional
Mdr 4 testpoints
0 2 4 6
Only if S.C. at acc. conditions NB! Matrixing og Bracketing

Intermediate Mdr. can be applied to reduce
amount of testing
Stability Protocol – Contents :-
◼ Name of the product
◼ Batch Size, type of Batch & No of Batches
◼ Source of API
◼ Type, Size, spurce of containers & Closures
◼ Storage Condition
◼ Sampling schedule
◼ Container storge orientation
◼ Test parameters
◼ Test Methods
◼ Acceptance Criteria
Std Storage Condition in accordance with ICH
Q1A(R2) & Q1F:-
Climatic Zones I & II Storage Condition Min Time Period covered by
data at submission
Long Term* 25c±2c/60%RH± 5%RH 12Months
or
30c± 2c/65%RH± 5%RH
Intermediate** 30c± 2c/65%RH± 5%RH 6 Months
Or
Accelerated Fallback
Accelerated 40c± 2c/75%RH± 5%RH 6 Months
Climatic Zones III & Iv
Long term 30c± 2c/65%RH± 5%RH 6 Months
Accelerated 40c± 2c/75%RH± 5%RH 6 Months
Brazil (August-2007) 30c± 2c/75%RH± 5%RH 3Months
Special Condition 25c/80%RH
e.g. Recommended solid dosage
forms in water-vapour
permeable packaging.
Contnud…….
◼ * It’s upto the applicant to decide whether long term stability studies
are performed @ 25c±2c/60%RH± 5%RH or 30c± 2c/65%RH± 5%RH
◼ ** If or 30c± 2c/65%RH± 5%RH Is the Long term condition, there’s
no intermediate condition.
◼ Note :- If “ Significant change” occurs during 6th month accelerated

study,additional testing at intermediate storage should be
conducted.the initial application should be 6th month data from 12
month study of intermediate storage condition.
◼ Drug Substances :- Failing to meet its specification.
Drug Substances intended for storage in Freezer:-
Study Storage Condition Min time period

covered by data at
submission
Long Term -20C ± 5C 12Months
Note :- It should be Eg :- Sensitive Note :- No

treated on a case by products, Accelerated study.
case basis. biotechnological
Product.
Drug Substances intended for storage in
a Refrigerator:-
Study Storage Condition Min time period

covered by data at
submission
Long Term 5C± 3C 12Months
Accelerated 25C± 2C/60%RH 6Months
Note :- If “ Significant change” occurs between 3 & 6 months

of the Accelerated study, data on long term study should be
submitted.
If “ Significant change” occurs within 3 months of the
Accelerated study, it’s unnecessary to continue further testing.
Std storage condition for Semi-Permeable &
impermeable packaging :
◼ Climatic Zones I & II Storage Condition Period
◼ Long Term* 25c±2c/40%RH± 5%RH

◼ or
12Months
◼ 30c± 2c/35%RH± 5%RH
◼ Intermediate**
◼ Or
6 Months
◼ Accelerated Fallback 30c± 2c/65%RH± 5%RH
◼ Accelerated 40c± 2c/NMT 25%RH 6 Months
◼ Climatic Zones III & Iv

◼ Long term 30c± 2c/35%RH± 5%RH 6 Months
◼ Accelerated 40c± 2c/NMT 25%RH 6 Months
◼ Note :- *It’s up to the applicant to decide whether Long term stability studies are performed at 25c±2c/40%RH± 5%RH
or 30c± 2c/35%RH± 5%RH.
◼ If 30c± 2c/35%RH± 5%RH is the long term condition , there’s no Intermediate condition.
◼ Semi-Permeable :- container that allow the passage of solvents, usuallu water,while preventing solute Loss.
◼ Eg ;- Lotion, SVPs, LVPs, Ophthalmological products in PE ampoules.
◼ Impermeable ;- Container that provide a permanent barrier to the passage of gases or solvents.
◼ Eg :- sealed aluminium tubes for semi-solids , sealed glass ampoules for solutions.
Tests parameters:-
◼ Parameters that are likely to influence quality,
safety/efficacy, If the products are to be
covered.
◼ 1. physical properties:- Colour, Clarity,
Particulate Matter.
◼ 2. Chemical properties :- Assay of Active,
Preservative, Degradation product.
◼ 3. Microbiological properties:- Sterility,
Pyrogenicity.
◼ 4. In accordance with ICH guideline(Q6A)on
Specification.
Test procedure :-
◼ 1. Analytical test procedures must be fully
validated.
◼ 2. Assay must be stability indicating.
◼ 3. Validation must include forced degradation
studies under different conditions. E.g.
Acid,Basic,Thermal, oxidation, hydrolysis &
photolytic degradation Etc.
◼ 4. Mass balance should be established (may
not be always 100%).
PHOTO STABILITY :-
Preamble :
The intrinsic photostability characteristics of new drug
substances & products should be evaluated to
demonstrate that, as appropriate, light exposure does
not result in unacceptable change.
◼ 1. Tests on the drug product.

◼ 2. Tests on the exposed drug product outside of the
immediate pack & if necessary,
◼ 3. Tests on the drug product in the immediate pack.
◼ 4. Tests on the drug product in the marketing pack.
PHOTO STABILITY :-
◼ B. Light Sources :- There are two options of light sources used for
photo stability.
◼ OPTION I :- Artificial daylight fluorecent lamp combining visible & UV

outputs, Xenon or metal halide Lamp
◼ OPTION II :- A cool white fluorecent lamp & a near UV fluorecent lamp

having a spectral emission range from 300nm to 400nm.
◼ Level of exposure for stability study:-
◼ Overall illumination of not less than 1.2 million Lux hours & an
integrated near UV energy of not less than 200 watt Hrs/m2. This can
be monitored by either Quinine actinometry, calibrated radiometers or
Lux meters.
◼ To exclude the thermal effect, a protected control sample(wrapped in
aluminium foil)may be exposed side by side.
COMMITMENT
➢ Initial long-term data on primary batches may not cover the
proposed shelf life granted at the time of approval.
➢ Commitment is made to continue the post approval studies
in order to firmly establish the shelf life.
➢ If the submission includes data from studies on less than 3
production batches, a commitment is made to continue the
long term studies during the proposed shelf life and place
additional production batches to make a total of at least 3
on long-term studies through the proposed shelf life.
➢ If the submission does not include stability data on
production batches, a commitment should be made to
place the first 3 production batches on long term studies
during the proposed shelf life and accelerated studies for 6
months.
EVALUATION OF STABILITY DATA TO ESTABLISH
SHELF LIFE - For Drug Products
RE-TEST DATE - For Drug Substances
If accelerated stability data for 6 months is OK.
x y
Accelerated Long Term y = 2x
(6months) (9 months OK) Shelf life / re-test date is 18 months
Accelerated Long Term y = 2x
Accelerated Long Term y = x + 12
Accelerated Long Term y = x + 12
Accelerated Long Term y=x
(6months) (36 months OK) No extrapolation beyond 36 months
EVALUATION OF STABILITY DATA TO ESTABLISH
SHELF LIFE - For Drug Products
RE-TEST DATE - For Drug Substances
If accelerated stability data for 6 months is NOT OK.
x y
Accelerated Intermediate y = 1.5x
(6months) 12 months OK Shelf life / re-test date is 18 months
Accelerated Intermediate y = 1.5x
(6months) 9 months OK Shelf life / re-test date is 13.5 months
Intermediate
Accelerated 9 months NOT OK y=x+3
(6months) & if long term Shelf life / re-test date is 12 months
9 months OK
STABILITY EVALUATION DATA
➢ Consider assay, degradation products & other appropriate attributes

for evaluation of stability study data.
➢ Use formal statistical analysis for data showing substantial

variability & degradation.
➢ Do not apply this statistical analysis for stability data showing little
degradation / variability.
➢ The nature of degradation relationship determines whether it should

be converted for linear regression analysis.
Significant changes in a Drug product
What does Significant change means……

◼ 1. A 5% change in Assay from ◼ Determining Water Loss :-
its initial value. ◼ 1. A 5 % loss in water from its
◼ 2. Any degradation product initial value is considered.
exceeds the set limits.
◼ 3. Failure to meet acceptance
criteria for appearance, physical
attributes or functionality tests. ◼ E.g 100 – Reference %RH /
E.g-colour, phase separation, 100 – Alternative % RH * Ratio
caking, hardness etc. of water loss rates at a given
temp.
◼ 4. Depending on the dosage
form, the pH value or
Dissolution rate no longer
satisfies the requirements. ◼ Zone Iv :- Alternative %RH -
◼ Drug Substances :- 75%RH. Reference %RH –
Failing to meet its specification. 25%RH. Ratio of water – 3.0
OOS/OOT analysis
FDA guidance on investigating OOS results
• Identifying and assessing OOS test results
• Responsibility of analyst
• Responsibilities of the supervisor
• Stability storage OOS issues
Investigating OOS results during stability testing

• Investigation guidance
• Laboratory phase of the investigation
• Re-testing
• Re-sampling
• Outlier results
• Interpretation of OOS results during stability testing
• Stability storage OOS issues
Difference between OOS and OOT

LABLELING CONSIDERATION FOR
DRUG PRODUCTS & DRUG SUBSTANCES
Statement / Labeling :
➢ A storage statement should be based on the stability
evaluation. Wherever applicable, specific instructions
should be provided. For eg.: drug substances that cannot
tolerate freezing.
➢ Avoid use of “ambient condition” or “Room temperature”.
➢ Need direct link between the label storage statement & the
demonstrated stability.
➢ A retest period for drug substance & expiration for the drug
product should be derived from stability information, and
should be displayed on the container label as appropriate.
LABLELING CONSIDERATION FOR
DRUG PRODUCTS & DRUG SUBSTANCES
Additional labeling
Testing conditions where Required labeling statement, where
stability has been shown statement relevant
25  20C / 60  5% RH (long term)
40  20C / 75  5% RH (accelerated)
or Do not refrigerate
None
30  2 C / 65  5% RH (long term)
0 or freeze.
40  20C / 75  5% RH (accelerated)
25  20C / 60  5% RH (long term)
Do not store above 30 0C
30  20C / 65  5% RH (intermediate) Do not refrigerate
or
or or freeze.
Store below 30 0C.
30  20C / 65  5% RH (long term)
Do not store above 25 0C Do not refrigerate

25  20C / 60  5% RH (long term)
or Store below 25 0C. or freeze.
5  30C (long term) Store in a refrigerator or Store Do not freeze.

& transport refrigerated.
Below zero Store in a freezer or Store & ---

transport frozen
OTHER SPECIFIC STORAGE STATEMENTS
Sr. Additional labeling statements*
No Storage problem depending on the packaging
1. Sensitivity to moisture. Keep the container*** tightly closed.

2. Sensitivity to moisture. Store in the original package.
3. Sensitivity to light.** Store in the original package.
4. Sensitivity to light.** Keep the container*** in the outer carton.
*An :explanation for the labeling statement should be

given in the package leaflet (e.g. “in order to protect
from light”) and on the outer packaging, where
space permits.
** :
Details of evaluation are included in the Committee
for Proprietary Medicinal Products (CPMP) /ICH
* ** :
Guideline on photo stability testing.
The actual name of the container should be used,
eg. Bottle, blister.
Part - I
CONCLUSION
➢ Re-test period for the drug substance & expiration

of drug product should be derived from stability
information & should be displayed on the container
label as appropriate.
➢ Avoid use of “ambient condition” or “room

temperature”. Be specific on the storage
temperature.
➢ In future, there may be only accelerated & long term

study since storage condition for both long term &
intermediate will remain same.
Part –IV
REDUCED DESIGN
BRACKETING AND MATRIXING

DESIGNS FOR STABILITY
TESTING OF DRUG SUBSTANCE
AND DRUG PRODUCT
ICH REFERENCE: Q1D

BRACKETING ICH REFERENCE: Q1D
OBJECTIVE
To provide guidance on application of Bracketing and Matrixing for
stability studies of Drug product and Drug substance.
What is Bracketing ?
Bracketing is the design of stability schedule such that only
samples of extremes of certain design factors (strength / container
size & / or fill) are tested at all points a sin full design. The design
assumes that the stability of any immediate levels is represented by
the stability of extremes tested.
The case of bracketing design would be considered appropriate if
design factors selected for testing are indeed the extremes.
Design Cinsideration &
Potential Risks:-
If the stability of the extremes is not

satisfactory, the intermediate should be
considered NO more stable than the
extremes.
BRACKETING Where it can be applied:
i. Capsules / tablets of different strengths, manufactured using the

same granules / powder (linear formulation) varying in different
quantity.
Examples :
Strength Powder fill / wt. of tab.
10 mg = 100 mg
20 mg = 200 mg
50 mg = 500 mg
II When the container size & fill volume vary. However, care should be
taken to select the extremes by comparing the various
characteristics of the container & closure system that may affect the
product stability, such as -
❑ Composition of container
❑ Wall thickness
❑ Head space to volume ratio
❑ Water vapor penetration rate, etc.
BRACKETING
III. Typical design example for bracketing:
1. FULL DESIGN STUDY:
Samples for every combination for all design
factors tested at all time points.
Strength 50 mg / 5 ml 75 mg / 5 ml 100 mg / 5 ml
Batch No. B1 B2 B3 B1 B2 B3 B1 B2 B3
Container 50 ml ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
Size 100 ml ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
500 ml ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
✓ : Data required (test to be performed)
III. BRACKETING - REDUCED DESIGN STUDY
Strength 50 mg / 5 ml 75 mg / 5 ml 100 mg / 5 ml
Batch No. B1 B2 B3 B1 B2 B3 B1 B2 B3
Container 50 ml ✓ ✓ ✓ X X X ✓ ✓ ✓
Size 100 ml X X X X X X X X X
500 ml ✓ ✓ ✓ X X X ✓ ✓ ✓
X Bracketing (test not necessary)
Example 2 :
Tablet range made with different compression weights of linear formulae.
Strength/tab. 25 mg 50 mg 100 mg 200 mg
Batch B1 B2 B3 B4 B5 B6 B7 B8 B9 B10 B11 B12
No.
100 s ✓ ✓ ✓ X X X X X X ✓ ✓ ✓
Containe
250 s X X X X X X X X X X X X
r Size
500 s ✓ ✓ ✓ X X X X X X ✓ ✓ ✓
X Bracketing (test not necessary)
WHAT IS MATRIXING ?
i. It is a stability schedule design.

ii. It is a selection of subset of the total number
of samples.
iii. It assumes all factor combinations tested at a
specified time point.
iv. The various factor combination to be
considered:
Ø Different batches.
Ø Different strengths.
Ø Different sizes of same containers.
Ø Different closure system.
• MATRIXING
When a secondary packing system contributes to the stability the drug
product matrixing can be performed across the packing system.
Design factors to be considered for Matrixing:
i. Strength of the dosage.
ii. Container size.
iii. Container fill.
In a matrix approach, a supporting data with respect to the effect due to:
➢ Moisture
➢ Light
➢ Oxygen
is required to prepare a design close to the ideal one.
Matrixing has a limited use in stability testing of Drug substance but it will
have significant applicability in drug products depending on strength,
container, closure fill volume, supporting data etc.
MATRIXING
Examples for sample Design:
(i) One half reduction-Matrixing

It eliminates one in every two points from the full
study design.
(ii) One third reduction- Matrixing
It eliminates one in every three points from the full

study design.
Part - II
ONE HALF REDUCTION - MATRIXING
Example: Matrix Design on time points for Product with two strengths.
If 48 study is to be conducted as per the table below.
Then, one half will be 24 and number of tests will be reduced 24/48.
Time point (months) 0 3 6 9 12 18 24 36
Strength S1 B1 T T X T T X T T
B2 T T X T T T X T
B3 T X T X T X T T
S2 B1 T X T X T X T T
B2 T T X T T T X T
B3 T X T X T X T T
T : Sample Tested
X Sample not tested
But in real, number of tests will be reduced by 15 & not 24.

This is mainly because of:
- Full testing of all factor combinations only at some frequency points.
- Example includes full testing at the initial, final and at the 12 months
point of time.
ONE THIRD REDUCTION- MATRIXING
Similarly in one third reduction, the number of tests will be
reduced 16/48.
Time point (months) 0 3 6 9 12 18 24 36
Strength S1 B1 T T X T T X T T
B2 T T T X T T X T
B3 T X T T T T T T
S2 B1 T X T T T T T T
B2 T T X T T X T T
B3 T T T X TT X T
T : Sample Tested
X Sample not tested
But in real, number of tests will be reduced by 10 & not 16.

This is mainly because of:
- Full testing of all factor combinations only at some frequency points.
- Example includes full testing at the initial, final and at the 12 months
point of time.
MATRIXING
III. COMPLEX DESIGNS:
i. Matrix design can be either complete or incomplete.
ii. In complete design all combination of factors are

tested.
iii. In incomplete design some combinations are not

tested.
MATRIXING
IV. APPLICABILITY:
While selecting the matrix following should be

considered:
➢ Data variability.
➢ The availability of supporting data.
➢ Any stability differences within the factor or
among the factors.
More the data available, more reduction is possible.

BRACKETING v/s. MATRIXING
❑ Bracketing and Matrixing is compliment to each other. Both the
techniques helps to reduce the design of various combination
factors based on strength, containers/ closures, fills and point of
testing time.
❑ Both Matrixing and Bracketing is a reduced design on different

principles.
❑ The use of Bracketing and Matrixing is generally applied

together.
❑ The design should be scientifically justified.
❑ BRACKETING IS GENERALLY NOT APPLICABLE TO DRUG

SUBSTANCE
• Bracketing is applicable to Drug product based on different
strengths, containers, closures and fill volumes.
➢ CONCLUSION
➢ Bracketing & Matrixing is a stability
schedule & a reduced design. The
number of test to be performed on a
different size, pack & strength should
be logically justified to reduce the
analytical load. Bracketing and
Matrixing is more applicable for drug
product.
IMPURITIES IN NEW DRUG SUBSTANCES
Classification of impurities:
i. Organic impurities (Process & Drug related).
ii. Inorganic impurities
iii. Residual Solvents
Identification threshold:
A limit above which an impurity should be identified.
Qualification threshold:
A limit above which an impurity should be qualified. Qualification
is the process of acquiring and evaluating data that establishes
biological safety of individual impurity level specified. The level of
any impurity present in a new drug substance that has been
adequately tested in safety and / or clinical studies would be
considered qualified
IMPURITIES IN NEW DRUG SUBSTANCES
Thresholds: (Drug substances)
Ma ximum daily Reporting Identification Qualification
dose (1) Threshold(2,3) Threshold (3) Threshold (3)
0.1% or 1 mg per day 0.15% or 1.0 mg
£ 2 gram per intake
0.05% per day intake
day
( whichever is low) (whichever is low)
>2 gram per
0.03% 0.05% 0.05%
day
1. The amount of the drug administered per day.

2. Higher reporting threshold should be scientifically justified.
3. Lower threshold can be appropriate if the impurity is
unusually toxic.
CONCLUSION
➢ Reporting, identifying &
qualifying of impurities are
based on the total daily
intake & the same has been
detailed in the ICH guideline.
• WHAT IS A SUPAC GUIDANCE?
• A communication that represents the best scientific judgement of

the Agency at this time regarding certain scale-up and post-
approval issues:
• TYPES OF SUPAC CHANGES
1. Components and Composition
2. Site Changes
3. Batch Size (Scale-Up/Scale-Down)
4. Manufacturing (Equipment/Process)
➢ Level I changes:
Which are unlikely to have any detectable impact on formulation
quality and performance
➢ Level II changes:
Which may have significant impact on formulation quality and
performance
➢ Level III changes:
Which have a significant impact on formulation quality and
performance.
SUPAC – Components and Composition changes:
Level Classification Documentation Suppleme
n
t
I • Complete or partial 1st production batch AR
deletion of colour / flavour on LTSS
• Change of excipient
ranges upto 5 %
II • Change in technical grade 1 batch with 3 month PAS
or specification of Acc data and LTSS
excipient data on 1st
• Change of excipient production batch
ranges upto 10%
III • Change of excipient 3 batches with 3 PAS
ranges exceeding 10 % months Acc data
and LTSS data on
1st 3 production
batches
SUPAC – Site changes:
Level Classification Documentation Supplem
ent
I • S a m e facility 1st p r o d u c t i o n b a t c h AR
• C o m m o n personnel o n L T S S (optional,
but recommended)
II • S a m e contiguous L T S S d a t a o n 1st CBE
campus Common production batch
personnel
III • Different c a m p u s 3 batches with 3 CBE
• Different personnel months Acc data
and LTSS data on
1st 3 p r o d u c t i o n
batches
SUPAC – Batch size changes:
Level Classification Documentation Supple
ment
I • Scale up of biobatch 1 st production batch AR
/ pivotal clinical batch on LT SS
(less than 10 X)
II • Scale up of biobatch 1 batch with 3 month CBE
/ pivotal clinical batch Acc data and LT SS
(More than 10 X) data on 1 st production
batch
SUPAC – manufacturing equipment changes:

ment
I • Equipment changes 1 st production batch AR
(same operating on LTSS
principle)
II • Equipment changes 3 batch with 3 month PAS
(different operating Acc data and LTSS
principle) data on 1 st 3
production batch
SUPAC – Manufacturing process changes:
ment
I • Adjustment within 1st production ba AR
operating conditions (eon LTSS (Optiona
Mixing time, speed wit recommended)
validated range)
II • Adjustments outside LTSS data onst1 CBE
operating conditions production batch
(outside the vdaaltied
range)
III • Change of process (e.g 3 batches with 3 PAS
Wet granulation to dire months Acc data
compression) and LTSS data on
1st 3 production
batches
Photo stability - Light source:
➢ Option 1: Artificial daylight fluorescent lamp combining visible
and UV outputs, xenon or metal halide lamp. or
➢ Option 2: A cool white fluorescent lamp & a near UV fluorescent
lamp having a spectral emission range from 320 nm to 400 nm
Level of exposure for stability study:
➢ Overall illumination of not less than 1.2 million lux hours and an
integrated near UV energy of not less than 200 watt hours/m2.
This can be monitored by either Quinine actinometry, calibrated
radiometers or lux meters.
➢ To exclude the thermal effect, a protected control sample
(wrapped in aluminum foil) may be exposed side by side.
Examples of stability problems from
the real life
1. Increased degradation due to impurities in excipients

2. Changes to drug substance process caused different degradation
pattern in drug product
3. Resuspension problems in suspensions
4. Analytical method not stability indicating
◼ Consequences of inadequate stability documentation or stability

problems:
Registration applications are delayed
(USA 1999: ~ 10% of NDA’s)
◼ Recalls
(USA 2001: > 25% of recalls are related to stability failures)
◼ Inspection observations
(USA 2001: 25 warning letters (36%) cited stability
problems)
◼ Mistakes in Documentation & Impact on Quality
◼ Wrong protocol number – SPP instead SSP
◼ Mismatching of the following
a) 1) API quantity In BMR for registration
2) API quantities in FP spec. of group 2 & group 3 countries
3) Acceptance criteria in stability study protocol.
b)Description, average weight, MC, test for impurities and microbial
load wrt to their specifications in acceptance criteria and annexure.
◼ Mistakes in calculation of average weight
◼ Not considered trend analysis data before finalizing the limit for DT –
soft gel caps.
◼ Annexure is for intermediate condition or ACC but the storage
condition written as RT .
◼ No inclusion of critical parameters like
◼ Hardness of tablets,
◼ Test for impurities,
◼ Microbial test for injections,
◼ Alcohol content in injections

strong training module for the recruited staff
I Scientific and Regulatory Aspects
• Importance of preparing and training personnel
• Significance of studies conducted
•Definition of shelf life, expiration dating, developmental, and
marketed product stability
• Determination of the storage conditions stability
• Definition of the roles of temperature, humidity, and light
• Key elements of stability testing
II. Stability Storage Chambers: Calibration, Monitoring, and
Maintenance
• Stability chambers and rooms used in the industry
• Installation, Operation, and Performance Qualifications
• Principles of calibration frequency and documentation
• Principles of monitoring frequency and documentation
• Maintenance of stability chambers
III. Stability Storage and Testing as Defined in cGMPs, ICH, and
FDA Guidelines
• CGMP requirements for stability storage and testing
• ICH stability guidelines’ expectations
• FDA guidelines’ expectations
• Photo stability studies
• Forced degradation (stress) and stability-indicating methods
Points for discussion:
◼ Assigning of protocol numbers
◼ Stability protocols: prepared by, reviewed &
approved by whom?
◼ Review of stability data
◼ Sharing of data
◼ Early identification of stability related issues
◼ Addressing stability issues
◼ Stability cell?
◼ SOPs for repeat testing for stability
◼ Review of all raw data by QA when compiling the
stability data
◼ Ensuring tractability of the data to records in the lab
– SOPs also is required
◼ Internal audit & review of stability data is mandatory
– create SOP accordingly
Understanding the regulations requirements.
Carefully following the SOP’s and timely updating the data at -
- each station after review of records.
Sharing the regular updates with internal customers
It isn’t easy sometimes… but we can do it !

Further questions ??????
◆http://www.who.int/medicines
◆www.fda.gov/cder/guidance/index.htm
◆ http:\\dg3.eudra.org
◆ www.ifpma.org/ich1.html
◆www.nihs.go.jp/dig/ich/ichindex.htm
◆ www.eudra.org/emea.html

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PRESENTATION ON ICH TOPICS &

GUIDELINES WITH A SPECIAL REFERENCE TO

• Part-I : Quality topics-Stability

◼ Aspects of Stability, that are to be considered include :

◼ To provide evidence on how the quality

◼ Why the stability testing is an important issue ?

UK Guidance notes on Applications for product 1984

Ethiopia Requirements of the registration of drugs 1986

4 segments based on environmental conditions

Designation Temperature Yearly Avg of

II Subtropical or 25°C 60%

III Hot & Dry 30°C 35%

IV Hot & 30°C 70%

American Chile, Canada Brazil,Jamaica,

African South Botswana, Ghana,

Australian/Ocean Australia,New Zealand Fiji, Papua,New-Guinea

Q1A(R2) Stability testing of new FEB-2003 Mar-2003 June-2003 Nov-2003

Q1A Q1A(R) Q1A(R2)

0, 3, 6, 9 & 12 0, 3, 6, 9 & 12 0, 3, 6, 9 & 12

0, 1, 2, 3 & 6 0, 3 & 6 0, 3 & 6

5 point study to 3 point study

Q1A Q1A(R) Q1A(R2)

30  20C / 30  20C / 30  20C /

40  20C / 40  20C / 40  20C /

Q1A Q1A(R) Q1A(R2)

Post Approval Clarity provided Clarity provided

• Stress testing •Formal •Follow-up

The testing should cover as appropriate : chemical, physical,

Long Term Mdr.

Only if S.C. at acc. conditions NB! Matrixing og Bracketing

◼ Note :- If “ Significant change” occurs during 6th month accelerated

Study Storage Condition Min time period

Long Term -20C ± 5C 12Months

Note :- It should be Eg :- Sensitive Note :- No

Study Storage Condition Min time period

Note :- If “ Significant change” occurs between 3 & 6 months

◼ Long Term* 25c±2c/40%RH± 5%RH

◼ Accelerated 40c± 2c/NMT 25%RH 6 Months

◼ Climatic Zones III & Iv

◼ 1. Tests on the drug product.

◼ OPTION I :- Artificial daylight fluorecent lamp combining visible & UV

◼ OPTION II :- A cool white fluorecent lamp & a near UV fluorecent lamp

◼ Level of exposure for stability study:-

STABILITY EVALUATION DATA

➢ Consider assay, degradation products & other appropriate attributes

➢ Use formal statistical analysis for data showing substantial

➢ The nature of degradation relationship determines whether it should

What does Significant change means……

Investigating OOS results during stability testing

Difference between OOS and OOT

Do not store above 25 0C Do not refrigerate

5  30C (long term) Store in a refrigerator or Store Do not freeze.

Below zero Store in a freezer or Store & ---

1. Sensitivity to moisture. Keep the container*** tightly closed.

*An :explanation for the labeling statement should be

➢ Re-test period for the drug substance & expiration

➢ Avoid use of “ambient condition” or “room

➢ In future, there may be only accelerated & long term

BRACKETING AND MATRIXING