Stabil Testing

Pharmaceutical Development with Focus on
Paediatric Formulations
WHO/FIP Training Workshop

Hyatt Regency Hotel
Sahar Airport Road
Andheri East, Mumbai, India
28 April 2008 – 2 May 2008
1| Dr. János Pogány | April 2008

Paediatric formulations
Presented by:
Name: Dr. János Pogány
Contact details:
pogany.janos@chello.hu

Outline of presentation
Regulatory issues on stability of APIs and FPPs
 Introduction
• Scientific approach to pharmaceutical stability
• Introduction to the new WHO Stability guideline
 Planning stability studies and reporting results
 Evaluation of stability results
 Risk-based inspection of stability studies
 Main points again

Paediatric formulations
.WHO working document QAS/06.179/Rev

DRAFT STABILITY TESTING OF ACTIVE
PHARMACEUTICAL INGREDIENTS AND
PHARMACEUTICAL PRODUCTS
INTRODUCTION

Scientific approach to stability
Vapor pressure (Pa) at different %RH

Temperature, oC
60 65 75
1900 2058 2375 25
2545 2757 3182 30
4425 4794 5531 40

Scientific approach to stability

WHO guidelines
„Stability of drug dosage forms” in 1990 initiated the global harmonization of
regulatory stability requirements
„Guidelines for stability testing of pharmaceutical products containing well
established drug substances in conventional dosage forms” (1996)
WHO amendment of the above guideline in TRS 937 (2006)
Working document QAS/06.179/Rev.2 – „Stability Testing of Active Pharmaceutical
Ingredients and Pharmaceutical Products” divides countries with tropical and
subtropical moist climates into:
– Zone IVA with long-term conditions: 30oC ± 2oC and 65% ± 5% RH
– Zone IVB with long-term conditions: 30oC ± 2oC and 75% ± 5% RH, which
is the worst case and the recommended long-term condition for the
Prequalification Project
Each individual Member State within the former Zone IV would need to
indicate whether its territory should be classified as Zone IVa or IVb

Selected definitions
Re-test period
After this period a batch of API destined for use in the manufacture of a
pharmaceutical product should be re-tested for compliance with the
specification and then used immediately. A batch of active pharmaceutical
ingredient can be re-tested multiple times and a different portion of the batch
used after each re-test, as long as it continues to comply with the specification.
A retest period should be proposed on the basis of stability results and may be
extended to five years (e.g., Ethambutol 2HCl, or Isoniazid)
For most biotechnological/biological substances known to be labile, it is more

appropriate to establish a shelf-life than a re-test period. The same may be true
for certain antibiotics.

Shelf-life (also referred to as "expiration dating period“)
The period of time during which a pharmaceutical product, if
stored correctly, is expected to comply with the specification as
determined by stability studies on a number of batches of the
product. The shelf-life is used to establish the expiry date of each
batch.


STABILITY PROTOCOLS AND

REPORTS
10 | Dr. János Pogány | April 2008

Protocol – regulatory requirement
 The ongoing stability programme should be described in a
written protocol and results formalized as a report. The protocol
should extend to the end of the re-test period and should include
parameters illustrated in slide 12
 The stability protocol used for long-term studies for the

stability commitment should be the same as that for the primary
batches, unless otherwise scientifically justified.

Stability protocol - API
Description Protocol Parameter
25°C/60% RH 0, 3, 6, 9, 12, (18, 24, 36) months Storage conditions (including
30oC/75% RH 0, 3, 6, 9,12, (18, 24, 36) months tolerances) and testing frequency
40°C/75% RH 0,3,6 months
L40438 (Jan. 2005), 80.50 kg Batch number and size
L50041 (Feb.2005), 69.00 kg
L50054 (March 2005), 73.00 kg
Simulated: double PE bags in black PE bag kept in Container closure system(s)
one-kg fiberboard drums well-closed
Assay by(98.0-102.0%), ImpA (NMT 0.15%), ImpB Tests and acceptance criteria
(NMT0.3%), and so on
Stress testing, including photostability testing Other(s)
according to ICH Q1B
The batches should be representative of the manufacturing process and should be
.manufactured from different batches of key intermediates

Stability protocol – oral suspension
25°C/60% RH 0, 3, 6, 9, 12, (18, 24, 36) months Storage conditions (including
30oC/75% RH 0, 3, 6, 9,12, (18, 24, 36) months tolerances) and testing frequency
40°C/75% RH 0,3,6 months
NEV40438 (Jan. 2007), 4000 bottles (960 liters) Batch numbers and size
NEV50439 (Jan.2007), 4000 bottles (960 liters)
NEV50440 (Jan. 2007), 4000 bottles (960 liters)
White HDPE bottle with two piece child-resistant Container closure system(s)
closure proposed for marketing
Assay (95.0-105.0%), there are no degradants, Tests and acceptance criteria
dissolution testing (and profile), in-use stability test,
preservative contents, antimicrobial preservative
effectiveness, re-suspendibility (sedimentation rate)
The batches should be representative of the manufacturing process and should be

manufactured from different batches of APIs. Executed manufacturing records and
certificates of analysis on the above batches should be submitted

Bracketing
 Stability studies should be performed on each individual strength, dosage
form and container size of the pharmaceutical product. If dosage form is
the same, then bracketing can be applied to:
 Different strengths (including FDC products)
– have identical formulations (including FDC products)
– are made with closely related formulations
 Container-closure system is the same and either the container size or the
fill size varies
 Even when the container-closure system varies bracketing is possible with
some justification. Such justification might be the demonstration that the
product is not water sensitive, or the discussion of the relative permeation
rates of the closure systems.

Bracketing design
Label strength and batch numbers (X,Y,Z)
30mg 20mg 10 mg
Pack type
Z Y X Z Y X Z Y X
+ + + - - - + + + Alu/Alu blister cards of 10 tablets
+ + + - - - + + + HDPE pack of 30 tablets
- - - - - - - - - HDPE pack of 100 tablets
+ + + - - - + + + HDPE pack of 1000 tablets

Matrixing
 Matrixing is the statistical design of a stability schedule .
 Each storage condition should be treated separately under its

own matrixing design
 At a given time point (other than the initial or final ones) not
every batch on stability needs to be tested
 Full testing must be performed at the maximum storage period

at the time of submission

Matrixing design
One-half matrix design – long-term stability studies
36 24 18 12 9 6 3 0 Testing station
+ + - + - - + + Batch 1
+ + - + + + - + Batch 2 S1
+ - + + - + - + Batch 3
+ - + + + + - + Batch 1
+ - + + - - + + Batch 2 S2
+ + - + + - + + Batch 3

A risk-based global stability protocol
Months
Storage conditions
36 24 18 12 9 6 3 0
+ + + + + + + 25oC ± 2oC and 60% ± 5% RH
- - - - - - - 30oC ± 2oC and 65% ± 5% RH
+ + + + + + + + 30oC ± 2oC and 75% ± 5% RH
+ + 40oC ± 2oC and 75% ± 5% RH
+ 50oC and ~70% RH
Source: Designing a globally acceptable registration stability protocol, Pharmaceutical Technology Europe, March 2007


STRESS TESTING

 Stress testing – API
Studies undertaken to elucidate the intrinsic stability of the
active pharmaceutical ingredient. Such testing is part of the
development strategy and is normally carried out under more
severe conditions than those used for accelerated testing.
 Stress testing – FPP

Studies undertaken to assess the effect of severe conditions on
the pharmaceutical product. Such studies include photostability
testing and specific testing on certain products, (e.g. metered
dose inhalers, creams, emulsions, refrigerated aqueous liquid
products).

ICH guidelines on stress testing
Title and reference Standard
Stability Testing of New Drug Substances and ICH Q1A(R2)

Products (the parent guideline)
Photostability Testing of New Drug Substances and ICH Q1B
Products
Validation of Analytical Procedures: Methodology ICH Q2B
Impurities in New Drug Substances ICH Q3A(R)
Impurities in New Drug Products ICH Q3B(R)

Stress testing
 To validate the stability indicating power of the analytical
procedures.
 To identify stability-affecting factors such as ambient
temperature, humidity and light and to select packing
materials, which protect the FPP against such effects.
 To identify potential degradants of the API and assess if they
can be formed during manufacture or storage of the FPP.
 To select manufacturing process of the FPP

Stress testing
Assay:
S1:
D1: A thin layer of the API is wetted with water
Total unspecified: and is kept at 80°C for 4 weeks in a Petri
Temperature
dish (open system) with sampling once a
week
Total impurities:
Assay:
A thin layer of the API is wetted with water
S1:
and kept at 40°C / 100% RH for 4 weeks in
D1: Humidity
a Petri dish (open system) with sampling
Total unspecified:
once a fortnight
Total impurities:
Assay: Oxygen is bubbled slowly through the
S1: oxygen-saturated aqueous
D1: solution/suspension (under constant mixing) Oxidation
Total unspecified: of the API for 24 hours with sampling every
Total impurities: eight (8) hours
Increase in concentration of API
During stability studies of Artesunate, the assay results were increasing. The
hydrolysis yields artenimol and succinic acid. The formation of succinic acid
justifies the increase in assay. The assay method is „stability indicating” but
not specific.

Stress testing (forced degradation)
Conditions Degradation factor

≥ 60 oC Thermal
≥ 75% RH Humidity
0.1N HCl Acid
0.1N NaOH Base
Oxygen gas, or 3% H2O2 Oxidative
Metal halide, Hg, Xe lamp, or UV-B fluorescent Photolytic
0.05M Fe2+ or Cu2+ Metal ions (optional)

Stress stability testing
 An optimal degradation pattern generated during stress testing
would show only those degradation products observed at the
end of shelf life in regulatory stability studies and those that
might appear if the API or FPP if not manufactured, handled or
packed properly.
 Chromatograms thus obtained will be representative and not too

complicated to evaluate, which may be the case if drastic
conditions are applied and many second- and third-generation
degradation products are formed.

Stress stability testing - Nevirapine
Assay (%) Conditions Stress type
99.8 25o C Control
72.0 80o C, 40 min. 36% HCl
98.6 80o C, 2h 20’ 5N NaOH
98.6 80o C, 2h 20’ 30% w/w H2O2
101.5 130o C, 49h Heat
101.7 500W/m2, 68h Light
101.2 25o C, 92% RH, 91h Water


PRESENTATION AND EVALUATION

OF RESULTS

Types of stability data
 Three types of data can be collected during stability studies
– reported as a single result such as assay, loss on drying, etc.
– data with multiple results such as dissolution testing
– third type is degradation product
 Most analytical laboratories will not quantify the result if it falls below the
LOQ. The value usually is reported as “˂ LOQ.”
 A special situation arises when a new peak forms during the analysis.
When a new peak forms during a stability study, one may expect that it
should not exist and hence it would constitute a type of OoT.
 If some of the results are below the LOQ value, if the assumption of
normality is not reasonable, or if linearity cannot be assumed, then an
attempt to identify OoT results using data from the same batch is not
recommended

Stability reports
 A systematic approach should be adopted in the presentation
and evaluation of the stability information, which should
include, as appropriate, results from the physical, chemical,
biological and microbiological tests, including particular
attributes of the dosage form
 The results should be presented both as a table and as a graph

and not as data sheets
 The Applicant should evaluate the stability data

Evaluation – Best Case
1. Tabulate and plot stability data on all attributes at all storage
conditions and evaluate each attribute separately.
2. No significant change at accelerated conditions within six (6)

months.
3. Long-term data show little or no variability and little or no

change over time.

Evaluation – Best Case
4. Accelerated data show little or no variability and little or no
change over time.
5. Statistical analysis is normally unnecessary and providing a

justification for the omission should be sufficient
6. Proposed retest period or shelf life = double of period covered

by long-tem data (X) but NMT X + 12 months
7. A retest period or shelf life granted on the basis of

extrapolation should always be verified by additional long-
term stability data

Is there a visible variability?
Nevirapine stability assay results in FDC tablets
(30±2°C/75±5%RH) (30±2°C/75±5%RH) (25±2°C/60±5%RH) Time
(Batch 08040003) (Batch 08040002) (Batch 08040001)
97.55 98.65 96.90 Initial, %
100.40 99.90 99.25 3M, %
99.55 99.05 99.20 6M, %
96.70 98.10 104.00 9M, %
101.30 101.30 99.30 12M, %
94.20 94.55 97.60 18M, %
98.95 101.40 100.20 24M, %
98.38 98.99 99.49 Mean, %
94.20 94.55 96.90 Minimum, %
101.30 101.40 104.00 Maximum, %
7.10 6.85 7.10 Range, %
2.43 2.33 2.28 STD
2.46% 2.35% 2.30% RSD

Analytical, sampling, process (control),
compliance alert?

Out-of-trend (OoT) results
 An OoT result is a stability result that does not follow the expected trend,
either in comparison with other stability batches or with respect to
previous results collected during a stability study.
 The identification of an OoT data point only notes that the observation is
atypical:
• within a batch
• across historical stability batches
 When an “odd-looking” stability pattern occurs, it is common to ask
whether the pattern reflects an underlying mechanism (i.e., a “cause”) or
is merely a normal process or analytical variation.
 Any out of trend/out of specification (OoT/OoS) observations
 “Do the data obtained so far indicate that the batch will go outside
specification during its shelf life?”

Out-of-trend (OoT) results
 Are all values above LOQ?
 Are all values below LOQ?
 Is a part of the data below LOQ?
 What is the analytical and sampling variation and a measured

characteristic's normal change over time?
 Timeliness is especially important when an analytical error is

suspected of causing OoT results

Significant change of FPPs
 A 5% change in assay from its initial value.
 Any degradation product exceeding its acceptance criterion.
 Failure to meet the acceptance criteria for appearance, physical

attributes, and functionality test (e.g., colour, phase separation,
hardness).
 As appropriate for the dosage form, e.g., failure to meet the

acceptance criteria for dissolution for 12 dosage units.

Reporting results
Observations of Accelerated Studies Test
E.g., conforms to specifications (white to off- white
Description
crystalline powder)
E.g., results ranged
range between 99.0-101.1 % (spec: 97.5-
Assay
102.0%); no visible trends or variability were observed
ImpA: ≤ 0.15%
ImpB: ≤ 0.1%
Any other unspecified Imp : ≤ 0.1% Related substances
Disregard any Imp ˂ 0.05%
Total impurities: ≤ 0.4%
Insert as many rows as necessary
Result sheets must bear date and responsible person’s signature / QA approval

SOP requirements
 A written stability-testing program to assess the stability
characteristics of drug products
 Review and investigation of OoT stability results
 Written procedures for conducting a thorough investigation of
any unexplained discrepancy
 A review of the OoT alert procedures' performance might
coincide with the annual product review
 The depth of an investigation and the corrective measures taken
may depend on the potential or implied risk to product quality

Evaluation – Change with Time
 An approach for analysing data on a quantitative attribute that is
expected to change with time is to determine the time at which
the 95% one-sided confidence limit for the mean curve
intersects the (lower) acceptance criterion (95% assay).
 The majority of degradation processes results in an essentially
linear line in this range of the label claim thus the method is
generally applicable for the estimation of the expiry date at the
studied storage conditions.
 The hypothetical figure in the next slide illustrates that the
extrapolated shelf life is 29 months (25oC/60%RH) and there is
only a 5% chance that this estimate will be high. Such a plot
covers assay values from 105% down to 95%.

ICH-Q1E Evaluation for Stability Data

Carstensen, J.T. – Drug stability

Evaluation – Change with Time*
The hypothetical figure in the former slide illustrates that the shelf
life is 24 months (at a given temperature). There is a 5% chance
that this estimate will be high. Such a plot covers potency values
from 100% down to 90%.
* DRUG STABILITY — Principles and Practices

Edited by Jens T. Carstensen and C. T. Rhodes
Third edition, revised and expanded (2000)
Marcel Dekker, Inc., 270 Madison Avenue, New York,

ICH-Q1E Evaluation for Stability Data

Evaluation – Change with Time
 The hypothetical figures in the former slides illustrate that the
shelf life is 31-32 months
 (25oC/60%RH) and there is only a 5% chance that this estimate

will be high. Such a plot covers degradant values from 0.6% up
to 1.4%.
 For FPPs in semipermeable containers, loss of vehicle can

result in an increase in the API concentration. In such cases, the
point where the upper 95% confidence bound intersects the
105% assay value will define the conformance period.

Stability results
 A storage statement should be proposed for the labeling (if
applicable), which should be based on the stability evaluation
of the API.
 A retest period should be derived from the stability information,

and the approved retest date should be displayed on the
container label.
 An API is considered as stable if it is within the defined/regulatory
specifications when stored at 30±2oC and 65±5% RH for 2 years and at
40±2oC and 75±5%RH for 6 months.

Post-approval protocol
30±2oC, 75±5% RH Storage conditions
Batches …. for 18,24,36 months
One additional production scale batch: 0, 3, 6, 9, 12, Testing frequency / Batches
18,24,36 months
Container closure system(s)
white to off white crystalline
Description
powder
98.0-102.0% Assay
Impurity 1 NMT 0.15%
Any unspecified NMT Tests and acceptance criteria
Related Substances
0.10%
Total: NMT 0.3%

Additional or New Stability Data
 Modifications affecting one or more steps of the same route of

synthesis of an API
 Change in the route of synthesis of an API
 Change in composition of the FPP
 Change in immediate packaging of the FPP

Main points again
 Stability studies should be planned on the basis of
pharmaceutical R+D and regulatory requirements.
 Forced degradation studies reveal the intrinsic chemical

properties of the API, while formal stability studies establish the
retest date.
 The shelf life (expiry date) of FPPs is derived from formal

stability studies.
 Variability and time trends of stability data must be evaluated by

the manufacturer in order to propose a retest date or expiry date.

THANK YOU!

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Pharmaceutical Development with Focus on

WHO/FIP Training Workshop

Sahar Airport Road

Andheri East, Mumbai, India

28 April 2008 – 2 May 2008

1| Dr. János Pogány | April 2008

Name: Dr. János Pogány

2| Dr. János Pogány | April 2008

3| Dr. János Pogány | April 2008

.WHO working document QAS/06.179/Rev

4| Dr. János Pogány | April 2008

Vapor pressure (Pa) at different %RH

5| Dr. János Pogány | April 2008

6| Dr. János Pogány | April 2008

7| Dr. János Pogány | April 2008

For most biotechnological/biological substances known to be labile, it is more

8| Dr. János Pogány | April 2008

9| Dr. János Pogány | April 2008

.WHO working document QAS/06.179/Rev

STABILITY PROTOCOLS AND

10 | Dr. János Pogány | April 2008

 The stability protocol used for long-term studies for the

11 | Dr. János Pogány | April 2008

12 | Dr. János Pogány | April 2008

The batches should be representative of the manufacturing process and should be

13 | Dr. János Pogány | April 2008

14 | Dr. János Pogány | April 2008

+ + + - - - + + + Alu/Alu blister cards of 10 tablets

+ + + - - - + + + HDPE pack of 30 tablets

- - - - - - - - - HDPE pack of 100 tablets

+ + + - - - + + + HDPE pack of 1000 tablets

15 | Dr. János Pogány | April 2008

 Each storage condition should be treated separately under its

 Full testing must be performed at the maximum storage period

16 | Dr. János Pogány | April 2008

17 | Dr. János Pogány | April 2008

18 | Dr. János Pogány | April 2008

.WHO working document QAS/06.179/Rev

19 | Dr. János Pogány | April 2008

 Stress testing – FPP

20 | Dr. János Pogány | April 2008

Stability Testing of New Drug Substances and ICH Q1A(R2)

Impurities in New Drug Substances ICH Q3A(R)

Impurities in New Drug Products ICH Q3B(R)

21 | Dr. János Pogány | April 2008

22 | Dr. János Pogány | April 2008

24 | Dr. János Pogány | April 2008

Conditions Degradation factor

0.05M Fe2+ or Cu2+ Metal ions (optional)

25 | Dr. János Pogány | April 2008

 Chromatograms thus obtained will be representative and not too

26 | Dr. János Pogány | April 2008

99.8 25o C Control

72.0 80o C, 40 min. 36% HCl

98.6 80o C, 2h 20’ 5N NaOH

98.6 80o C, 2h 20’ 30% w/w H2O2

101.5 130o C, 49h Heat

101.7 500W/m2, 68h Light

101.2 25o C, 92% RH, 91h Water

27 | Dr. János Pogány | April 2008

.WHO working document QAS/06.179/Rev

PRESENTATION AND EVALUATION

28 | Dr. János Pogány | April 2008