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
Pharmaceutical Development with Focus on
Paediatric formulations
Presented by:
Name: Dr. János Pogány
Contact details:
pogany.janos@chello.hu
2|
Dr. János Pogány | April 2008
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
3|
Dr. János Pogány | April 2008
Pharmaceutical Development with Focus on
Paediatric formulations
WHO working document QAS/06.179/Rev.
DRAFT STABILITY TESTING OF ACTIVE
PHARMACEUTICAL INGREDIENTS AND
PHARMACEUTICAL PRODUCTS
INTRODUCTION
4|
Dr. János Pogány | April 2008
Scientific approach to stability
Vapor pressure (Pa) at different %RH
Temperature,
5|
oC
75
65
60
25
2375
2058
1900
30
3182
2757
2545
40
5531
4794
4425
Dr. János Pogány | April 2008
Scientific approach to stability
6|
Dr. János Pogány | April 2008
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
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Dr. János Pogány | April 2008
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.
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Dr. János Pogány | April 2008
Selected definitions
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.
9|
Dr. János Pogány | April 2008
Pharmaceutical Development with Focus on
Paediatric Formulations
WHO working document QAS/06.179/Rev.
DRAFT STABILITY TESTING OF ACTIVE
PHARMACEUTICAL INGREDIENTS AND
PHARMACEUTICAL PRODUCTS
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.
11 |
Dr. János Pogány | April 2008
Stability protocol - API
Protocol Parameter
25°C/60% RH
Storage conditions (including
tolerances) and testing frequency 30oC/75% RH
Batch number and size
Container closure system(s)
Tests and acceptance criteria
Other(s)
Description
0, 3, 6, 9, 12, (18, 24, 36) months
0, 3, 6, 9,12, (18, 24, 36) months
40°C/75% RH
0,3,6 months
L40438 (Jan. 2005), 80.50 kg
L50041 (Feb.2005), 69.00 kg
L50054 (March 2005), 73.00 kg
Simulated: double PE bags in black PE bag kept in
one-kg fiberboard drums well-closed
Assay by(98.0-102.0%), ImpA (NMT 0.15%), ImpB
(NMT0.3%), and so on
Stress testing, including photostability testing
according to ICH Q1B
The batches should be representative of the manufacturing process and should be
manufactured from different batches of key intermediates.
12 |
Dr. János Pogány | April 2008
Stability protocol – oral suspension
Protocol Parameter
Description
Storage conditions (including
25°C/60% RH 0, 3, 6, 9, 12, (18, 24, 36) months
tolerances) and testing frequency 30oC/75% RH 0, 3, 6, 9,12, (18, 24, 36) months
40°C/75% RH 0,3,6 months
Batch numbers and size
NEV40438 (Jan. 2007), 4000 bottles (960 liters)
NEV50439 (Jan.2007), 4000 bottles (960 liters)
NEV50440 (Jan. 2007), 4000 bottles (960 liters)
Container closure system(s)
White HDPE bottle with two piece child-resistant
proposed for marketing
closure
Tests and acceptance criteria
Assay (95.0-105.0%), there are no degradants,
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
13 |
Dr. János Pogány | April 2008
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.
14 |
Dr. János Pogány | April 2008
Bracketing design
Label strength and batch numbers (X,Y,Z)
10 mg
Pack type
20mg
30mg
X
Y
Z
X
Y
Z
X
Y
Z
Alu/Alu blister cards of 10 tablets
+
+
+
-
-
-
+
+
+
HDPE pack of 30 tablets
+
+
+
-
-
-
+
+
+
HDPE pack of 100 tablets
-
-
-
-
-
-
-
-
-
HDPE pack of 1000 tablets
+
+
+
-
-
-
+
+
+
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Dr. János Pogány | April 2008
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
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Dr. János Pogány | April 2008
Matrixing design
One-half matrix design – long-term stability studies
Testing station
0
3
6
9
12
18
24
36
Batch 1
+
+
-
-
+
-
+
+
S1 Batch 2
+
-
+
+
+
-
+
+
Batch 3
+
-
+
-
+
+
-
+
Batch 1
+
-
+
+
+
+
-
+
S2 Batch 2
+
+
-
-
+
+
-
+
Batch 3
+
+
-
+
+
-
+
+
17 |
Dr. János Pogány | April 2008
A risk-based global stability protocol
Months
Storage conditions
3
6
9
12
18 24 36
25oC ± 2oC and 60% ± 5% RH
+
+
+
+
+
+
+
30oC ± 2oC and 65% ± 5% RH
-
-
-
-
-
-
-
+
+
+
+
+
+
+
40oC ± 2oC and 75% ± 5% RH
+
+
50oC and ~70% RH
+
30oC ± 2oC and 75% ± 5% RH
0
+
Source: Designing a globally acceptable registration stability protocol, Pharmaceutical Technology Europe, March 2007
18 |
Dr. János Pogány | April 2008
Pharmaceutical Development with Focus on
Paediatric Formulations
WHO working document QAS/06.179/Rev.
DRAFT STABILITY TESTING OF ACTIVE
PHARMACEUTICAL INGREDIENTS AND
PHARMACEUTICAL PRODUCTS
STRESS TESTING
19 |
Dr. János Pogány | April 2008
Selected definitions
 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).
20 |
Dr. János Pogány | April 2008
ICH guidelines on stress testing
Standard
21 |
Title and reference
ICH Q1A(R2)
Stability Testing of New Drug Substances and
Products (the parent guideline)
ICH Q1B
Photostability Testing of New Drug Substances and
Products
ICH Q2B
Validation of Analytical Procedures: Methodology
ICH Q3A(R)
Impurities in New Drug Substances
ICH Q3B(R)
Impurities in New Drug Products
Dr. János Pogány | April 2008
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
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Dr. János Pogány | April 2008
Stress testing
23 |
Temperature
A thin layer of the API is wetted with water
and is kept at 80°C for 4 weeks in a Petri
dish (open system) with sampling once a
week
Humidity
A thin layer of the API is wetted with water
and kept at 40°C / 100% RH for 4 weeks in
a Petri dish (open system) with sampling
once a fortnight
Oxidation
Oxygen is bubbled slowly through the
oxygen-saturated aqueous
solution/suspension (under constant mixing)
of the API for 24 hours with sampling every
eight (8) hours
Dr. János Pogány | April 2008
Assay:
S1:
D1:
Total unspecified:
Total impurities:
Assay:
S1:
D1:
Total unspecified:
Total impurities:
Assay:
S1:
D1:
Total unspecified:
Total impurities:
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.
+
24 |
Dr. János Pogány | April 2008
Stress testing (forced degradation)
Degradation factor
Conditions
Thermal
≥ 60 oC
Humidity
≥ 75% RH
Acid
0.1N HCl
Base
0.1N NaOH
Oxidative
Oxygen gas, or 3% H2O2
Photolytic
Metal halide, Hg, Xe lamp, or UV-B fluorescent
Metal ions (optional)
0.05M Fe2+ or Cu2+
25 |
Dr. János Pogány | April 2008
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.
26 |
Dr. János Pogány | April 2008
Stress stability testing - Nevirapine
Stress type
27 |
Conditions
Assay (%)
Control
25o C
99.8
36% HCl
80o C, 40 min.
72.0
5N NaOH
80o C, 2h 20’
98.6
30% w/w H2O2
80o C, 2h 20’
98.6
Heat
130o C, 49h
101.5
Light
500W/m2, 68h
101.7
Water
25o C, 92% RH, 91h
101.2
Dr. János Pogány | April 2008
Pharmaceutical Development with Focus on
Paediatric Formulations
WHO working document QAS/06.179/Rev.
DRAFT STABILITY TESTING OF ACTIVE
PHARMACEUTICAL INGREDIENTS AND
PHARMACEUTICAL PRODUCTS
PRESENTATION AND EVALUATION
OF RESULTS
28 |
Dr. János Pogány | April 2008
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
29 |
Dr. János Pogány | April 2008
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
30 |
Dr. János Pogány | April 2008
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.
31 |
Dr. János Pogány | April 2008
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 longterm stability data
32 |
Dr. János Pogány | April 2008
Is there a visible variability?
Time
Initial, %
3M, %
6M, %
9M, %
12M, %
18M, %
24M, %
Mean, %
Minimum, %
Maximum, %
Range, %
STD
RSD
33 |
Nevirapine stability assay results in FDC tablets
(25±2°C/60±5%RH)
(30±2°C/75±5%RH)
(30±2°C/75±5%RH)
(Batch 08040001)
(Batch 08040002)
(Batch 08040003)
96.90
98.65
97.55
99.25
99.90
100.40
99.20
99.05
99.55
104.00
98.10
96.70
99.30
101.30
101.30
97.60
94.55
94.20
100.20
101.40
98.95
99.49
98.99
98.38
96.90
94.55
94.20
104.00
101.40
101.30
7.10
6.85
7.10
2.28
2.33
2.43
2.30%
2.35%
2.46%
Dr. János Pogány | April 2008
Analytical, sampling, process (control),
compliance alert?
34 |
Dr. János Pogány | April 2008
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?”
35 |
Dr. János Pogány | April 2008
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
36 |
Dr. János Pogány | April 2008
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.
37 |
Dr. János Pogány | April 2008
Reporting results
Test
Observations of Accelerated Studies
Description
E.g., conforms to specifications (white to off- white
crystalline powder)
Assay
E.g., results ranged between 99.0-101.1 % (spec: 97.5102.0%); no visible trends or variability were observed
ImpA: ≤ 0.15%
ImpB: ≤ 0.1%
Related substances Any other unspecified Imp : ≤ 0.1%
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
38 |
Dr. János Pogány | April 2008
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
39 |
Dr. János Pogány | April 2008
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%.
40 |
Dr. János Pogány | April 2008
ICH-Q1E Evaluation for Stability Data
41 |
Dr. János Pogány | April 2008
Carstensen, J.T. – Drug stability
42 |
Dr. János Pogány | April 2008
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,
43 |
Dr. János Pogány | April 2008
ICH-Q1E Evaluation for Stability Data
44 |
Dr. János Pogány | April 2008
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.
45 |
Dr. János Pogány | April 2008
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.
46 |
Dr. János Pogány | April 2008
Post-approval protocol
Protocol Parameter
Storage conditions
Description
30±2oC, 75±5% RH
Batches …. for 18,24,36 months
Testing frequency / Batches One additional production scale batch: 0, 3, 6, 9, 12,
18,24,36 months
Container closure system(s)
Description
Assay
Tests and acceptance criteria
47 |
Dr. János Pogány | April 2008
Related Substances
white to off white crystalline
powder
98.0-102.0%
Impurity 1 NMT 0.15%
Any unspecified NMT
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
48 |
Dr. János Pogány | April 2008
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.
49 |
Dr. János Pogány | April 2008
THANK YOU!
50 |
Dr. János Pogány | April 2008