ICH guidelines -1.pdf good to have understanding

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: EuropeanAgency for the evaluation of Medicinal products
• EFPIA: European Federation of Pharmaceutical Industries & associations
• FDA: Food and DrugAdministration
• PhRMA: Pharmaceutical Research and Manufacturers ofAmerica
• MHLW: Ministry of Health, Labour Welfare
• JPMA: Japan Pharmaceutical ManufacturersAssociation

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
◼ T
o 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
licenses
1984
Zimbabwe Guidelines for the stability testing 1985
Ethiopia Requirements of the registration of drugs
for human use
1986
USA Submitting documentation for the stability
of Human Drugs & biologics
1987
European union Stability testing on Active ingredients &
Finished products
1988

Global climatic zones:
4 segments based on environmental conditions

Classification according to four
Climatic Zones
Temperature
(MKT C)
Yearly Avg of
RH %
Designation
I Moderate 21°C 45%
II Subtropical or
Mediterenean
25°C 60%
III Hot & Dry 30°C 35%
IV Hot &
Humidity
30°C 70%

Distribution of Nation into
different Climatic Zones :-
Zones I & II Zones III & IV
Regions
European & Uk All Countries -
American Chile, Canada
United States
Brazil,Jamaica,
Venezuela
Asian China,Japan,
Turkey
India,Philippines,Sri
Lanka
African South
Africa,Zambia,Zimbabwe
Botswana, Ghana,
Uganda
Australian/Ocean Australia,New Zealand Fiji, Papua,New-Guinea

ICH Drug Stability Guidelines
Code Guideline Finalised
ICH
Ad opted By
CPMP MHLW USFDA
Q1A(R2) Stability testing of new
drug Substances &
Products
FEB-2003 Mar-2003 June-2003 Nov-2003
Q1B Photostability testing of
new Drug
Substances/Products
Nov-1996 Dec-1996 May-1997 May-1997
Q1C Stability testing of new
dosage forms
Nov-1996 Dec-1996 May-1997 May-1997
Q1D Bracketing & matrixing
Designs for stability
testing of new drug
substances/ Products
Feb-2002 Feb-2002 July-2002 Jan-2003
Q1E Evalution of Stability
Data
Feb-2003 Mar-2003 June-2003 June-2004
Q5C Stability testing of
Biotechnological/biolog
ical products
Nov-1995 Dec-1995 Jan-1998 July-1996
Q1F Stability testing of
Biotechnological/biolog
ical products
Withdrawal
-June-2006
- - -

Q1A Q1A(R) Q1A(R2)
Testing Frequency
Long Term
0, 3, 6, 9, 12,18,
24, … .months
0, 3, 6, 9, 12,18,
24, … .months
0, 3, 6, 9, 12,18,
24, … .months
0, 3, 6, 9 & 12 0, 3, 6, 9 & 12 0, 3, 6, 9 & 12
months months months
0, 1, 2, 3 & 6 0, 3 & 6 0, 3 & 6
months months months
Intermediate
Accelerated
PROGRESSIVE CHANGES IN ICH GUIDELINE
CHANGE
5 point study to 3 point study

Q1A Q1A(R) Q1A(R2)
25  20C /
60  5% RH
25  20C /
60  5% RH
25  20C/ 60  5% RH
or 30  20C/65  5% RH
(Decision is left to
the applicant)
Stability Storage
Condition
Long Term
30  20C /
60  5% RH
30  20C /
60  5% RH
30  20C /
65  5% RH
Intermediate
40  20C /
75  5% RH
40  20C /
75  5% RH
40  20C /
75  5% RH
Accelerated
CHANGE
CHANGE

Q1A Q1A(R) Q1A(R2)
Stress Testing Glossary
Body of the
guideline
Body of the
guideline
CHANGE
Post Approval
Commitment Ambiguous Clarity provided
for the commitment
CHANGE
Clarity provided
for the commitment
Specification
No cross
Testing
Procedure
reference
available
Cross reference
*Q6A & Q6B
Cross reference
*Q6A & Q6B
Acceptance No cross
Criteria reference
available
Cross reference
*Q6A & Q6B
Cross reference
*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
Development
Submission
and Approval
Post-approval
• Stress testing
• Photostability
• Studies to support
process & product
development
•Clinical trial stability
• Shipping and
In-use stability
•Intermediates
•Formal
studies
for the
application
• Commitmen
t batches
•Follow-up
stability
program
•Stability
studies initiated
by:
- Changes
- Deviations

Stress Testing for Drug
Substances & Product:-
◼
◼
◼
◼
◼
◼ To be carried out on a single batch of the drug
substances.
It can help to identify the likely degradation
products which can help to establish:-
i. The degradation path way.
Ii. The intrinsic stability of the molecule.
Iii. Valdate the stability indicating power of the
analytical procedures used.
Photo stability testing should be an integral part
of stress testing.
◼ Classification of API according to stability :-
◼ Sum of
Degradatio
1.
2.
3.
4.
Category
Products:-
Very Stable(s)
Stable (s)
Unstable (I)
Very Unstable (I)
<LOQ*
LOQ*-1.5%
1.5%-10.0%
>10%
A. General:- The Design of the stability
program for the finished product should
be based on the knowledge of the
behaviour & properties of the drug
substances & the experience gained
from clinical formulation studies & from
the stability studies on the drug
substances.

◼ Batches to be tested:
Guide Applicability Min. no.
of batch
Size & type
line
ICH New drug substances 3 Pilot scale
New drug products 3 2 pilot scale, 1
smaller
WHO Products containing easily degradable
actives
3 Pilot o full scale
production
Products containing established and
stable substances
2 Different production
batches
•Ongoing stability No.of batches WHO 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
forms and drug products without
significant body of information
3 2 pilot scale, 1
smaller
CPMP Existing active substances 2 or 3 Production scale
Conventional dosage forms containing
stable actives
2 Pilot scale
Critical dosage forms (prolonged
release forms) or when active
substances are known to be unstable
3 2 pilot scale, 1
smaller

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
specifications:
”…include those attributes
of the drug product/drug
substance that are
susceptible to change
during storage and likely to
influence quality, safety
and/or efficacy”
End shelf life ( Stability)
specification
The likely changes on
storage and the rationale for
the selection of attributes to
be tested in the formal
stability studies should be
stated”

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
3
Long Term
(25°C/60%RH) 0
6 9 12 18 24 36
Mdr.
Mdr.
xtra testing
Mdr
Mdr.
Mdr.
Duration: Minimum
full shelf-life
Yearly
thereafter
4 testpoints
Optional
NB! Matrixing og Bracketing
can be applied to reduce
amount of testing
Data at submission
Accelerated
(40°C/75%RH) 0
6
Accelerated
if significant 0 3
change is expected
(40°C/75%RH)
0 2 4
3
6
E
6
Only if S.C. at acc. conditions
Intermediate

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) &
Climatic Zones I & II
Q1F:-
Storage Condition Min Time Period covered by
data at submission
Long Term* 25c±2c/60%RH± 5%RH
or
30c± 2c/65%RH± 5%RH
12Months
Intermediate**
Or
Accelerated Fallback
30c± 2c/65%RH± 5%RH 6 Months
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.

◼ * 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.
Contnud…….

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
treated on a case by
case basis.
Eg :- Sensitive
products,
biotechnological
Product.
Note :- No
Accelerated study.

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*
◼
◼
◼ Intermediate**
◼ Or
◼ Accelerated Fallback
25c±2c/40%RH± 5%RH
or
30c± 2c/35%RH± 5%RH
30c± 2c/65%RH± 5%RH
12Months
6 Months
◼ 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.

➢ 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.
COMMITMENT

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
(6months)
Long Term
(9 months OK)
y = 2x
Shelf life / re-test date is 18 months
Accelerated
(6months)
Long Term
(12 months OK)
y = 2x
Accelerated
(6months)
Long Term
(18 months OK)
y = x + 12
Accelerated
(6months)
Long Term
(24 months OK)
y = x + 12
Accelerated
(6months)
Long Term
(36 months OK)
y = x
No extrapolation beyond 36 months

x y
Accelerated
(6months)
Intermediate
12 months OK
y = 1.5x
Accelerated
(6months)
Intermediate
9 months OK
y = 1.5x
Shelf life / re-test date is 13.5 months
Accelerated
(6months)
Intermediate
9 months NOT OK
& if long term
9 months OK
y = x + 3
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.

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
◼ 1. A 5% change in Assay from
its initial value.
◼ 2. Any degradation product
exceeds the set limits.
◼ 3. Failure to meet acceptance
criteria for appearance, physical
attributes or functionality tests.
E.g-colour, phase separation,
caking, hardness etc.
◼ 4. Depending on the dosage
form, the pH value or
Dissolution rate no longer
satisfies the requirements.
◼ Drug Substances :-
Failing to meet its specification.
◼ Determining Water Loss :-
◼ 1. A 5 % loss in water from its
initial value is considered.
◼ E.g 100 – Reference %RH /
100 – Alternative % RH * Ratio
of water loss rates at a given
temp.
◼ Zone Iv :- Alternative %RH -
75%RH. Reference %RH –
25%RH. Ratio of water – 3.0
What does Significant change means……

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

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

LABLELING CONSIDERATION FOR
DRUG PRODUCTS & DRUG SUBSTANCES
Required labeling
statement
Additional labeling
statement, where
relevant
Testing conditions where
stability has been shown
25  20C / 60  5% RH (long term)
40  20C / 75  5% RH (accelerated)
or
30  20C / 65  5% RH (long term)
40  20C / 75  5% RH (accelerated)
None
Do not refrigerate
or freeze.
25  20C / 60  5% RH (long term)
30  20C / 65  5% RH (intermediate)
or
30  20C / 65  5% RH (long term)
Do not store above 30 0C
or
Store below 30 0C.
Do not refrigerate
or freeze.
25  20C / 60  5% RH (long term)
Do not store above 25 0C
or Store below 25 0C.
Do not refrigerate
or freeze.
5  30C (long term) Store in a refrigerator or Store
& transport refrigerated.
Do not freeze.
Below zero Store in a freezer or Store &
transport frozen
---

space permits.
for Proprietary Medicinal Products (CPMP) /ICH
Guideline on photo stability testing.
The actual name of the container should be used,
eg. Bottle, blister.
*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
* * :
Details of evaluation are included in the Committee
* ** :
Sr.
No Storage problem
Additional labeling statements*
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.
OTHER SPECIFIC STORAGE STATEMENTS

CONCLUSION
Part - I
➢ 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.
of “ambient condition” or
Be specific on the
“room
storage
➢ Avoid use
temperature”.
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
10 mg
20 mg
50 mg
Powder fill / wt. of tab.
= 100 mg
= 200 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.

all design
III. Typical design example for bracketing:
1. FULL DESIGN STUDY:
Samples for every combination for
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
Size
50 ml ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
100 ml ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
500 ml ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
✓ : Data required (test to be performed)
BRACKETING

III. BRACKETING - REDUCED DESIGN STUDY
Strength/tab. 25 mg 50 mg 100 mg 200 mg
Batch
No.
B1 B2 B3 B4 B5 B6 B7 B8 B9 B10 B11 B12
Containe
r Size
100 s ✓ ✓ ✓ X X X X X X ✓ ✓ ✓
250 s X X X X X X X X X X X X
500 s ✓ ✓ ✓ X X X X X X ✓ ✓ ✓
X Bracketing (test not necessary)
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
Size
50 ml ✓ ✓ ✓ X X X ✓ ✓ ✓
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.

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.

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.
MATRIXING

ONE HALF REDUCTION - MATRIXING
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.
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.
T i m e p o i n t ( m o n t h s ) 0 3 6 9 1 2 1 8 2 4 3 6
S t r e n g t h S 1 B 1 T T X T T X T T
B 2 T T X T T T X T
B 3 T X
X
T X
X
T X
X
T T
S 2 B 1 T T T T T
B 2 T T X T T T X T
B 3 T X T X T X T T
T : S a m p l e T e s t e d
X S a m p l e n o t t e s t e d
Part - II

0 3 6 9 12 18 24 36
T T X T T X T T
B2 T T
B3 T
T X T T X T
T T T T T T
X
X
B2 T T
Time point (months)
Strength S1 B1
S2 B1 T
B3 T T
T T T T T T
X T T X T T
T X T T X T
Similarly in one third reduction, the number of tests will be
reduced 16/48.
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.
ONE THIRD REDUCTION- MATRIXING

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.

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.
MATRIXING

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
load. Bracketing and
is more applicable for drug
analytical
Matrixing
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

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.
IMPURITIES IN NEW DRUG SUBSTANCES
Thresholds: (Drug substances)
Ma ximum daily Reporting Identification Qualification
dose (1) Threshold(2,3) Threshold (3) Threshold (3)
£ 2 gram per
day
0.05%
0.1% or 1 mg per day
intake
( whichever is low)
0.15% or 1.0 mg
per day intake
(whichever is low)
>2 gram per
day
0.03% 0.05% 0.05%

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
deletion of colour / flavour
• Change of excipient
ranges upto 5 %
1st
production batch
on LTSS
AR
II • Change in technical grade
or specification of
excipient
• Change of excipient
ranges upto 10%
1 batch with 3 month
Acc data and LTSS
data on 1st
production batch
PAS
III • Change of excipient
ranges exceeding 10 %
3 batches with 3
months Acc data
and LTSS data on
1st
3 production
batches
PAS

SUPAC – Site changes:
L e v e l C l a s s i f i c a t i o n D o c u m e n t a t i o n S u p p l e m
e n t
I • S a m e f a c i l i t y
• C o m m o n p e r s o n n e l
1 s t
p r o d u c t i o n b a t c h
o n L T S S ( o p t i o n a l ,
b u t r e c o m m e n d e d )
A R
I I • S a m e c o n t i g u o u s
c a m p u s C o m m o n
p e r s o n n e l
L T S S d a t a o n 1 s t
p r o d u c t i o n b a t c h
C B E
I I I • D i f f e r e n t c a m p u s
• D i f f e r e n t p e r s o n n e l
3 b a t c h e s w i t h 3
m o n t h s A c c d a t a
a n d L T S S d a t a o n
1 s t
3 p r o d u c t i o n
b a t c h e s
C B E

Level Classification Documentation Supple
ment
I • Scale up of biobatch 1st
production batch AR
/ pivotal clinical batch
(less than 10 X)
on LTSS
II • Scale up of biobatch
/ pivotal clinical batch
(More than 10 X)
Acc data and LTSS
data on 1st
production
batch
CBE
SUPAC – Batch size changes:
ment
I • Equipment changes
(same operating
principle)
1st
production batch
on LTSS
AR
II • Equipment changes
(different operating
principle)
Acc data and LTSS
data on 1st
3
production batch
PAS
SUPAC – manufacturing equipment changes:

SUPAC – Manufacturing process changes:
ment
• Adjustment within
operating conditions (eon LTSS (Optiona
Mixing time, speed wit recommended)
validated range)
I 1st
production ba AR
II • Adjustments outside
operating conditions
(outside the vdaaltied
range)
production batch
LTSS data onst
1 CBE
III
compression)
Wet granulation to diremonths Acc data
and LTSS data on
1st
3 production
batches
• Change of process (e.g3 batches with 3 PAS

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.

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
(USA2001: 25 warning letters (36%) cited stability
problems)
Examples of stability problems from
the real life

◼ 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 QAwhen 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

ICH guidelines -1.pdf good to have understanding

ICH guidelines -1.pdf good to have understanding

More Related Content

What's hot (20)

Similar to ICH guidelines -1.pdf good to have understanding (20)

Recently uploaded (20)

ICH guidelines -1.pdf good to have understanding