Evaluation of Quality and Interchangeability of
Medicinal Products
Training Workshop for Evaluators
from National Medicines Regulatory
Authorities in East African
Community
Dar Es Salaam, Tanzania
Date: 10 to 14 September 2007
Slide 1 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Evaluation of Quality and Interchangeability of
Medicinal Products
Finished Pharmaceutical Products
Presenter:

Stability/Shelf-life specification

Matrixing and bracketing
Deus K. Mubangizi, pharmacist, MSc(Pharm.)
deuskm@yahoo.co.uk, dmubangizi@nda.or.ug
Chief Inspector of Drugs, National Drug Authority
WHO expert
Slide 2 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.1.
Manufacturing and marketing authorization
3.2.
Pharmaceutical development
3.3.
Formulation
3.4.
Sites of manufacture
3.5.
Manufacturing process
3.6.
Manufacturing process controls of Critical steps and intermediates
3.7.
Process validation and Evaluation
3.8.
Specifications for excipients
3.9.
Control of the FPP
3.10. Container/closure system (s) and other packaging
3.11. Stability testing
Slide 3 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.12. Container labelling
3.13. Product information for health professionals
3.14. Patient information and package leaflet
3.15. Justification for any differences to the product in the country
countries issuing the submitted WHO-type certificate(s)
Slide 4 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
or
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.11. Stability testing
The purpose of stability testing is to provide evidence on how the
quality of a FPP varies with time under the influence of a
variety of environmental conditions such as temperature,
humidity and light and to establish a shelf-life for the FPP,
to determine the storage conditions and the in-use stability.
To know about length of the time and conditions where efficacy,
safety and quality of the FPP are maintained
Slide 5 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.11. Stability testing

Lots included in the study: 1 production batch and 2 of pilot scale manufactured
according to the process described in the dossier

Pilot scale batch for solid dosage forms is 10% of production scale or
100 000 whichever is greater

Parameters susceptible to change over storage should be followed:
Organoleptic properties
Assay of each API: ±10% of the label claim possible at the end of shelf-life
Assay of degradation products
Assay of antioxidants and chemical preservatives, check also for their efficacy
Dissolution testing (limits should remain unchanged to release)
Microbial contamination, sterility, bacterial endotoxins

In-use stability data (if applicable)
Slide 6 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.11. Stability testing

Study should be performed in the claimed commercial packaging
(container-closure)

Storage conditions and frequency of testing according to ICH Q1A(R2)

Minimum stability data to be submitted at time of submission: 12
months long term ICH 25°C/60% RH, 12 months intermediate ICH
30°C/65% RH and 6 months accelerated ICH 40°C/75% RH with
exception according to Supplement 2 to the Main Generic guide

Unless otherwise justified, 30°C / 65% RH is the recommended storage
condition for Prequalification

Definition of "significant change" is the same as ICH Q1A (R2)
see later slide
Slide 7 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.11. Stability testing

Case of products packed in semi-permeable containers foreseen (liquid
dosage forms susceptible to loss of solvent or water loss in low relative
humidity condition). The storage condition will be long term ICH 25°C
/ 40% RH and accelerated 40°C/25% RH

Extrapolation of data to accord a longer shelf-life possible according to
ICH Q1E + Supplement 2 in condition of commitments

Supplement 2: tentative 2 year re-test period and /or shelf-life may be
accorded to APIs and corresponding solid forms (tablets and capsules)
listed in Supplement 2 based only on 6 months accelerated data and 6
months long term data

Long term stability should anyhow be followed to cover the whole
shelf-life accorded
Slide 8 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
SPECIFICATIONS
 Should include those attributes that are susceptible to
change during storage and are likely to influence quality,
safety and/or efficacy
 Should cover as appropriate, the physical, chemical,
biological and microbiological attributes, preservative
content and functionality tests (e.g. for a dose delivery
system)
 Analytical procedures should be fully validated and
stability indicating
 Shelf life acceptance criteria should be derived from
consideration of all available stability information
Slide 9 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
SPECIFICATION cont’
 Justifiable differences between the shelf life and release
acceptance criteria based on evaluation of stability data
and changes observed on storage
 Any differences between release and shelf life acceptance
criteria for antimicrobial preservative content to be
supported by development data
 A single, primary stability batch should be tested for
antimicrobial preservative effectiveness (in addition to
preservative content) whether there is a difference
between the release and shelf life acceptance criteria for
preservative content or not
Slide 10 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
TESTING FREQUENCY
 Long-term conditions : every 3 months over the first year,
every 6 months over the second year and annually
thereafter
 Accelerated storage conditions: minimum of 3 points
including the initial and final time points (e.g. 0, 3, & 6
months) from a 6-month study
 When testing at the intermediate storage condition is
called for as a result of significant at the accelerated
storage condition, a minimum of 4 time points, including
the initial and final time points (e.g. 0, 6, 9 & 12 months)
from a 12-month study is recommended.
 Reduced designs i.e. matrixing or bracketing can be
applied, if justified
Slide 11 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
STORAGE CONDITIONS
 Thermal stability, and if applicable, sensitivity to moisture or
potential for solvent loss
 The storage conditions and lengths of studies chosen to cover
storage, shipment and subsequent use
 Stability testing of the finished product after constitution or dilution
to labelling, storage condition and in-use period of the constituted or
diluted product
 Long term studies : minimum of 6 months duration (1st option) and
12 months (2nd option) at the time of submission and should be
continued for a period of time sufficient to cover the proposed shelf
life
Slide 12 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
STORAGE CONDITIONS cont’
General Case
STUDY
STUDY CONDITION
MIN TIME PERIOD
Long term*
25±2ºC/60±5%RH or
6 months (option 1)
30±2ºC/65±5%RH
12 months (option 2)
Intermediate
30±2ºC/65±5%RH
6 months
Accelerated
40±2ºC/75±5%RH
6 months
* It is up to applicant to decide whether long term stability studies are conducted at
either of the conditions. If 30±2ºC/65±5%RH is chosen, then no additional data
under intermediate conditions will be generated
Slide 13 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
STORAGE CONDITIONS cont’
If “significant change” occurs under accelerated studies, additional
testing at the intermediate storage condition required
 A “significant change” can be defined as
–A 5% change in assay from its initial value
–Any degradation product exceeding its acceptance criterion
–Failure to meet acceptance criteria for appearance, physical attributes, or
functionality tests (e.g. colour, phase separation, resuspendability, caking,
hardness, dose delivery per actuation)
Some changes in physical attributes (e.g. softening of suppositories, melting of
creams, partial loss of adhesion for transdermal products) may be expected
under accelerated conditions
Slide 14 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
IN-USE STABILITY TESTING
 The content of multi-dose containers, due to repeated opening and
closing
 A minimum of 2 batches, at least pilot scale batches, should be
subjected to the test. At least one should be chosen towards the
end of its shelf-life
 Test design should simulate the use of the product in practice
including fill volume, dilution/constitution before use
 The determined in-use shelf life should be stated on the label
Slide 15 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
IMPERMEABLE CONTAINERS
 Sensitivity to moisture or potential for solvent loss is not of
concern as there is a permanent barrier to passage of
moisture or solvent
 Therefore stability studies for products stored in
impermeable containers can be conducted under any
controlled or ambient humidity conditions
Slide 16 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
FFP IN SEMI-PERMEABLE CONTAINERS
 Aqueous based products packaged in semi-permeable containers
should be evaluated for potential water loss
 Studies should be carried out at low relative humidity to
demonstrate that container can withstand low relative humidity
environments
A 5% water loss is considered significant after an equivalent of
3months at 40±2ºC/ NMT 25%RH; however for small container
i.e. 1ml or unit-dose products, this may be appropriate if
justified
Slide 17 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
FFP INTENDED FOR REFRIDGERATOR
STORAGE
STUDY
STUDY CONDITIONS
MIN. TIME PERIOD
Long term
5 ± 3ºC
6 months (option 1)
12 months (option 2)
Accelerated
25±2ºC/60±5%RH
6 months
Significant change after 3-6months under accelerated the proposed
shelf life should be based on real-time data
Discussion should be provided to address the effects of short term
excursions e.g. during shipment supported by testing of a single batch
for a period shorter than 3 months but with more frequent testing than
usual
Slide 18 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
STABILITY COMMITMENT
 When available long-term stability data does not cover the
proposed shelf life, a commitment should be made to continue
stability studies in order to firmly establish the shelf life
– Such data should be submitted once available
 Where the data submitted is from fewer than 3 production batches,
a commitment should be made to continue the long-term studies
with additional production batches, to a total of at least 3
 If the submission does not include data on production batches, a
commitment should be made to place the first 3 production batches
on long-term studies through the proposed shelf life and through
6months of accelerated study conditions
Slide 19 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
EVALUATION
 A systematic approach to presentation and evaluation of
the data
 Degree of variability of individual batches to be evaluated
 Where the data show little degradation and variability that
it is apparent from looking at the data that the requested
shelf life can be granted, it is not necessary to go through
formal statistical analysis
 Evaluation should not be limited to assay, but
consideration of degradation products, appropriate
attributes, adequacy of the mass balance and different
stability and degradation performance
Slide 20 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Extrapolation of data
Limited extrapolation of the real-time data from long-term studies
beyond the observed range to extend the shelf life may be applied on
condition that:
- mechanisms of degradation are known
- results of accelerated stability testing are
available
- there is goodness of fit of any mathematical
model to be used
- supporting stability data exists
The assumption is that the same degradation relationship will continue
to apply beyond the observed data
Slide 21 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
SHELF LIFE
 The expiration period of a product should be calculated
from the date of release of that batch
 The date of release should, under normal circumstances,
not exceed 30days from the date of production
 If batches are released exceeding 30days from the
production date, the date of production i.e. the date that
the first step is performed involving combining the active
with the other ingredients, should be taken as the start of
the shelf life
Slide 22 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
STABILITY TESTING –
BRACKETING & MATRIXING
INTRODUCTION
 It is possible to reduce the scheduled test points where
the stability of the samples tested represents the stability
of all the products in the range being assessed
 This allows the saving of resources whilst providing
acceptable proof of stability
Slide 24 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
DEFINITIONS
 BRACKETING
The design of a stability schedule such that at any time point, only the
samples on the extremes e.g. of container size and/or dosage
strengths are tested.
The design assumes that the stability of the intermediate condition samples is
represented by the extremes
 MATRIXING
The statistical design of a stability schedule so that only a fraction of
the total number of samples are tested at any specified sampling
point. At a subsequent sampling point, different sets of samples of
the total number would be tested. The design assumes that the
stability of the samples tested represents the stability of all the
samples
Slide 25 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
PRECONDITIONS
 The concept of using a reduced testing plan is acceptable only for
products which are closely related
 Where either bracketing or matrixing are used, the stability testing
protocol should be justified by making use of stability data for both
the API and the finished product
 To justify bracketing around batches, it should be shown that batch
to batch variability is small
 It should be implied that not all the batches have to be started
simultaneously i.e. the batches could be staggered compared to
each other and the start of analysis
Slide 26 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
APPLICATION
 BRACKETING
Can be used for the testing of a new drug product available
in 3 different strengths, in 2 types of packaging material
and for one of these types, three different pack sizes
PACK TYPE
DOSAGE STRENGTH
50MG
75MG
A
B
C
Blister
x
x
x
HDPE/15
x
x
HDPE/100
(x) (x)
HDPE/500
x
x
A
B
100MG
C
A
B
C
(x)
(x) (x)
x
x
x
x
(x)
(x) (x)
x
x
x
(x)
(x)
(x) (x)
(X) (x)
x
(x)
(x) (x)
x
Slide 27 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
x
(x)
x
APPLICATION
 MATRIXING
– It provides a systematic test protocol which ensures that ALL product
strengths, types of packaging materials, pack size etc, are tested to THE
SAME EXTENT.
– Unlike bracketing, none of the product strengths, pack sizes, or product
variants are excluded from testing
– The applicant should demonstrate that the design is valid and will ensure that
the testing of all variables is approximately evenly distributed (use of statistical
programs)
Slide 28 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
ACCEPTANCE
 It will normally be acceptable to apply bracketing or matrixing in the
following cases:
Strength (small or no change in proportion of ingredients); strength
(where these are applied simply changing/varying the amount of
active and one or two major ingredients); container size (same
contact materials); closure systems of demonstrated equivalence;
different manufacturing sites (same company); batch size
 In the following cases applying matrixing will normally be
acceptable
Strength (significant change in proportion of ingredients or change in
one or two minor components; orientation of container; fill volumes
of containers; containers (different contact materials); closure
systems (non-equivalent performance); manufacturing process;
manufacturing site (different company)
Slide 29 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007
THANK YOU
Slide 30 of 30 D.K. Mubangizi, Dar Es Salaam Sept. 2007