1. اللهم صلي وسلم على سيدنا محمد
بسم الله الرحمن الرحيم
اللهم صلي وسلم على سيدنا محمد
STABILITY STUDY and EXPIRATION DATE R
aculty of Pharmacy
كلية الصيدلة F
Alaa Khedr Ph.D.
Professor
Faculty of Pharmacy
King Abdulaziz University
Abstract
The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, and enables recommended storage conditions, re-test periods and shelf lives to be established.
The choice of test conditions defined in this guideline is based on an analysis of the effects of climatic conditions in the three areas of the EC, Japan and the USA. The mean kinetic temperature in any region of the world can be derived from climatic data.

2. Abbreviations API Active Pharmaceutical Ingredient
FDC Fixed-Dose Combination
FPP Finished Pharmaceutical Product
GMP Good Manufacturing Practices
ICH International Conference on Harmonization
MA Marketing Authorization
DRA Drug Regulatory Authority
MCA: Medicine Control Agency
FDA: Food and Drug Administration
NDA: New Drug Applications
ANDA: Abbreviated New Drug Applications
EU: European Union
EMEA: European Medicinal Evaluation Agency
CPMP: Committee for Proprietary Medicinal Products
NTA: Notices To Applicant
CDER / CFR: Code of Federal Register

3. Applicable guidelines
Guidance for Industry
Q1A(R2) Stability Testing of New Drug Substances and Products
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
November 2003, ICH
Q1E Evaluation of Stability Data
June 2004, ICH 

4. Objectives Degradation Prod. 4.5% Drug 100% Drug 95.5% + Time (month)
1- The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, and enables recommended
 (1) storage conditions, (2) re-test periods and (3) shelf lives to be established.
Temp.
Humidity
Light
Drug 95.5%
Drug
100% +
Time
(month)
Degradation Prod.
4.5%
2- Safety and efficacy.

5. Before starting program execution we should have;
Design
Before starting program execution we should have;
Specification of Product
All SOP’s
Equipment & tools
Stability Protocol
Compendia
& Company Spcs
Approved Docs
IQ/OQ/PQ,
Data Logger
Log sheets
Written/Approved
Stability Indicating
Analytical Method
Drug product
Reference Standards
ICH Stress testing
Development
Validation
Represent. Chromatograms
Purchase USP / Europ. RS
Purchase Potential Impurities
Storage cabinet
Verified
Batch size
3 batches
Sampling protocol

6. Before starting program execution we should have;
Design
Before starting program execution we should have; 1
Stability Protocol
Written/Approved
Who doing what? How to do the task
Clear interpretation of procedures
Stepwise manner
Stability protocol is a signed/dated and approved document that describe the exact and clear procedure to start the stability testing of drug. The procedure should be described in a sequential stepwise manner, who doing what, how to do the task.

7. Before starting program execution we should have;
Design
Before starting program execution we should have; 2
Specification of Product
All SOP’s
Info. Source 1 = Compendia (USP/BP)
Info. Source 2 = FDA / ICH guidelines (Limits / general Official Procedure)
Info. Source 3 = Supplier of raw material
Info. Source 4 = Company approved specs of API and PFP

8. Before starting program execution we should have;
Design
Before starting program execution we should have; 3
Equipment & tools
IQ/OQ/PQ,
Data Logger
Log sheets
Documentations are available = IQ/OQ/PQ
Data Logger (calibrated) = Temp., Humidity
Documents = Log sheets of operation, time, date
How to operate the machine = SOP for machine

9. UV HPLC Dissolution Stability Cabinets Karl Fisher Balances3
Equipment & tools
+ Data loggers !!!! UV
HPLC
Dissolution
Stability Cabinets
Karl Fisher
Balances
Calibrated Glassware

10. Stability Cabinets A special cabinet for each condition3
Equipment & tools
+ Data loggers !!!!
Stability Cabinets
A special cabinet for each condition
Should be qualified / calibrated
Monitor Temp. / humidity vs time. Time
Three General conditions required.
Deep freeze 
 Data loggers

11. sensor probe / thermocouple
Data Loggers (Types)
sensor probe / thermocouple

12. Why we use Data Loggers ? How many sensor probe? How to position sensors?
To monitor Both, temperature and Relative Humidity along 24 hours.
To ensure consistency of the adjusted Temp. and RH.
Should be calibrated by supplier
Any deviation for NLT 6 hours, we should stop study and repeat using new samples.
Ex: Electricity shutdown, or instrument failer, no enough water inside instrument.

13. Photostability Cabinets3
Equipment & tools
Photostability Cabinets
At least one primary batch
Should be tested
Why we defined some products to be photosensitive, to which degree ?
(use UV-A, 200 watts hours/m2 )
Illumination   : 1.2 million Lux hours
Humidity range   : 40% to 95% ± 2% RH
Temperature range    : 100c to 500C, ± 0.50C
-- Use calibrated machine (candles/inch = ?)
3. Exposure time limit = ?
(according to the limit of potential degradation products formed, and quinine HCl standard)

14. Before starting program execution we should have;
Design
Before starting program execution we should have; 4
Stability Indicating
Analytical Method
ICH Stress testing
Development
Validation
Represent. Chromatograms

15. Stability indicating Analytical Method
The method is able to discriminate between principle drug
and the degradation products and/or impurities
Method: Compendial methods are claimed to be stability indicating
Rules: ICH stress Guideline
Plus: Photodegradation products & reconstitution testing
Monitoring: Peaks of Potential impurities &
Degradation products (previously define the cause)

16. Example of STRESS TESTING OF BETAHISTINE HCl
Rules of Stress testing:
-- expose drug subs. To abnormal environmental variables.
-- Forced degradation to NLT 90%.
-- Do not degraded the drug completely ? To provide selectivity of the method.
heated
NaOH
HCl
Representative chromatograms of betahistine hydrochloride; heated in solid state [a], boiled in 1M NaOH [b], boiled with 1M HCl [c], extracted from tablet powder exposed to UV light [d], extracted from Betaserc tablets [e], and left to stand in 0.1% H2O2 solution [f].
UV light
Betaserc tablets
H2O2

17. Analytical Method Performance
Chromatographic parameters* of TIA degraded with 1M HCl, (detection; UV at 254 nm, claimed TIA concentration is 250 ng/μL). n = 3.
RT (min)
(RSD)
Area
Width
(min)
% Amount
± SD
K ‘ R α As N
12.31
(0.14)
(0.06)
0.83
48.60
±0.01
5.15
1.11
20393
21.37
(0.02)
694064
(0.88)
0.70
7.32
±1.02
9.68
11.82
1.88
1.32
107053
28.05
(0.27)
(0.75)
1.07
18.55
±0.68
13.03
7.57
(0.26)
1.35
1.29
59909
29.17
(0.15)
601828
(0.58)
0.85
6.34
±1.33
13.59
1.17
(0.12)
1.04
1.19
152496
30.54
(0.11)
(0.55)
0.73
18.92
±1.20
14.27
1.73
(0.08)
1.05
1.20
157276
32.57
(1.20)
18284
(1.00)
0.47
0.19
±0.66
15.28
3.37
(0.95)
1.13
189448
33.49
7442
(0.65)
0.38
0.08
±0.34
15.74
2.17
(0.01)
1.03
191957
* k’ capacity factor; α, selectivity coefficient; R, resolution; and As, peak asymmetry; N, USP plate count.
How to present the analytical HPLC
method PERFORMANCE PARAMETERS

18. What are the
Stability-indicating quality parameters
Stability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy.
For instance, in case of tablets:
♦ appearance ♦ hardness
♦ friability ♦ moisture content
♦ dissolution time ♦ degradants
♦ assay ♦ microbial purity

19. Before starting program execution we should have;
Design
Before starting program execution we should have; 5
Drug Product
Batch size
3 batches
Sampling protocol

20. Selection of batches: 5 Drug product
How many batches should be tested ?
Batch size = ? Product unit
Which Batches should be tested ?
When should we repeat stability testing?

21. Selection of batches: 5 Drug product
How many batches should be tested ?
three, using 3 different batches of starting drug substance
Batch size = ? Product unit
Two pilot scale batches, third smaller if justified)
Which Batches should be tested ?
Stability studies should be performed on each individual strength and container size.
When we should repeat stability testing?
[1]
In case of failed stability ..!
[2] Modification?
using raw material from different manufacturer,
excepients  type/ratio change
manufacturing procedure  modified.
change of  package, closure.
[3]
Application
For ANDA
(Pharm. Bioeq) !!

22. Container / closure systems:
The stability testing should be conducted on the dosage form stored in the proposed containers / closure system for marketing.

23. Before starting program execution we should have;
Design
Before starting program execution we should have; 6
Reference Standards
Purchase USP / Europ. Reference Standard)
Purchase Potential Impurities
Stored in Special Storage cabinet + log book (amount used, when, for what?)
Verified (Melting point, IR, HPLC-RT as per USP/BP)

24. Major Variables Temperature Relative Humidity Light (Photostability)
Stability after Reconstitution (dilution)

25. Typical storage condition and study duration
[a] General Case (PERMEABLE)
[b] Drug Products packaged in IMPERMEABLE containers
[c] Drug Products packaged in SEMIPERMEABLE containers
[d] Drug Products intended for storage in refrigerator
[e] Drug Products intended for storage in freezer
[f] Drug Products intended for storage below -20 ºC

26. Frequency of sampling (months)
Typical storage condition and study duration
[a] General Case (PERMEABLE containers to moisture)
Study
Storage condition
Minimum time period
Frequency of sampling (months)
Long-term
252C / 60 % RH  5% RH or
302C / 65 % RH  5% RH
12 months
0,3,6,9,12,18,24
Intermediate
6 months
0,3,6,12
Accelerated
402C / 75 % RH  5% RH
0,1,2,3,6
It is up to the applicant to decide the tem/RH for long term.
If 302C / 65 % RH  5% RH is the long term, then NO INTERMEDIATE cond.

27. Frequency of sampling (months)
Typical storage condition and study duration
[b] Drug product packaged in IMPERMEABLE containers
(to moisture or solvent loss)
Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged in impermeable containers that provide a permanent barrier to passage of moisture or solvent.
Thus, stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition.
Study
Storage condition
Minimum time period
Frequency of sampling (months)
Long-term
252C or
302C
12 months
0,3,6,9,12,18,24
Intermediate
6 months
0,3,6,12
Accelerated
402C
0,1,2,3,6

28. Frequency of sampling (months)
Typical storage condition and study duration
[c] Drug products stored in SEMIPERMEABLE containers
Study
Storage condition
Minimum time period
Frequency of sampling (months)
Long-term
252C / 40% RH  5% RH or
302C / 35% RH  5% RH
12 months
0,3,6,9,12,18,24
Intermediate
302C / 65 % RH  5% RH
6 months
0,3,6,12
Accelerated
402C / NMT 25 % RH
0,1,2,3,6
It is up to the applicant to decide the tem/RH for long term.
If 302C / 35% RH  5% RH is the long term, then NO INTERMEDIATE cond.
Aqueous-based products packaged in semipermeable containers should be evaluated for potential water loss in addition to physical, chemical, biological, and microbiological stability.
5% loss of water (after 3 months) is considered significant change.

29. Frequency of sampling (months) Frequency of sampling (months)
Typical storage condition and study duration
[d] Drug products intended for storage in a REFRIGERATOR
Study
Storage condition
Minimum time period
Frequency of sampling (months)
Long-term
5 3C
12 months
0,3,6,9,12,18,24
Accelerated
252C / 60 % RH  5% RH
6 months
0,1,2,3,6
[e] Drug products intended for storage in FREEZER
Study
Storage condition
Minimum time period
Frequency of sampling (months)
Long-term
-20 5C
12 months
0,3,6,9,12,18,24
[f] Drug products intended for storage BELOW -20 C
Drug products intended for storage below -20°C should be treated on a case-by-case basis.

30. THE SIGNIFICANT CHANGES

31. THE SIGNIFICANT CHANGE IS DEFINED AS

32. Example of Failed stability
The assay value is still within the limits but the change during stability is more than 5.0%
Example
Release assay limit: 95.0 – 105.0%
Release assay: % (within spec)
6-Month assay: 95.5% (within spec)
Loss in potency: %.
This is a significant change.

33. Stability Data and Report

34. Stability Data and Report
attaché Real Chromatograms
attaché Records
Ex: Karl fisher data, tablet weight. .
Attaché auto dissolution readings
Attaché Cabinet temp./RH chart data.
Batches tested
Product name.
Name and potency of active ingredient.
Validated Stability indicating assay method
Batch size.
Batch number.
Manufacturing site.
Manufacturing date.
Date stability study was started.
Date sample(s) was withdrawn from chamber.
Date of sample analysis.
Storage conditions (e.g., 40C / 75% RH).
Container / closure system.
Supplier and manufacturer of active ingredient(s).
Supplier and manufacturer of container / closure system.
Supplier and manufacturer of packaging components, cartons, etc.
Cumulative tabulation of all tests result.
Literature review
Records, reports, and certificates
Conclusion, QA approval and Decision

35. Additional or New Stability Data is Required if;
Change in the route of synthesis of an API
Change in composition of the FPP
Change in immediate packaging of the FPP
In case of failed stability, (chemical, instrumental, regulatory)
using raw material from different manufacturer,
excepients  type/ratio change
manufacturing procedure  modified.
change of  package, closure.

36. و الحمد لله رب العالمين
Thank you