.WHO - Stability - Testing. 2007

Pharmaceutical Development
Training Workshop on
Pharmaceutical Development with
focus on Paediatric Formulations
Tallinn
15-19th October 2007
Training Workshop on Pharmaceutical Development

Slide 1
with a Focus on Paediatric Medicines 15-19 October 2007
Stability testing of Finished

Pharmaceutical Products (FPPs)
Presenter: Susan Walters
Email: susanw@netspeed.com.au
Fax: (61) 2 6281 6948 (email is preferred)

Slide 2
Stability testing of FPPs
Outline of presentation
We will:
 Review relevant guidelines
 Define the objectives of stability testing
 Outline the design & conduct of stability studies for finished

products
 Determine a shelf life based on study results
 Discuss what to include in reports of stability studies

Slide 3
Objectives of stability testing:
What is the purpose?
 "…… 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 & light, & enables recommended
storage conditions, re-test periods & shelf lives to be
established”
ICH Q1A (2003)

Slide 4
Variables that might affect the stability of a given
API & dosage form
 Formulation
 Packaging
 Site and method of manufacture

– API
– Finished product
 Batch size
 Batch to batch variability

– The importance of process validation & quality risk management
 Container labelling
 Changes to product

Slide 5
Stability testing
- Development studies
- Characterise compatibility with common excipients
- Characterise stability profile of API
- Eg susceptibility to acid, base, light, oxygen etc……
- Characterise stability profile of early formulations
- Especially susceptibility to heat, humidity & light
- Confirmatory studies
- Long term & accelerated studies on the product as it is to be registered
- In practice design is now largely dictated by ICH guidelines

Slide 6
What does a regulator want to see demonstrated in
the registration dataset?
- The product maintains relevant quality

characteristics within the acceptable range:
- In proposed registration formulation & container/closure system
- For whole of shelf life
- At permitted extremes of storage
- Over all batches
- When manufactured at all registered sites (API & finished
product)
- After any changes

Slide 7
Relevant guidelines
 Many countries have their own guidelines concerning stability testing & other
registration topics
 But if a manufacturer wishes to market a product in several countries, it is
simpler to use one of the international guidelines, such as those of WHO &
ICH
So how widely are WHO & ICH guidelines accepted?
 Most countries will accept data generated according to ICH guidelines
 Many countries will accept data generated according to WHO guidelines, &
especially when the product in question has been prequalified by WHO
– But possibly not ICH countries
 Whilst ICH guidelines are more detailed than those of WHO, there are few
‘in-principle’ differences, except in relation to testing conditions for hot &
humid climates

Slide 8
ICH stability guidelines - 1
 Q1A(R2) Stability Testing of New Drug Substances

& Products
 Q1B Stability Testing : Photostability Testing of

New Drug Substances & Products
 Q1C Stability Testing for New Dosage Forms
Available via
http://www.ich.org/cache/compo/276-254-1.html

Slide 9
 Q1D Bracketing and Matrixing Designs for Stability

Testing of New Drug Substances and Products
 Q1E Evaluation of Stability Data
 Q1F Stability Data Package for Registration

Applications in Climatic Zones III and IV Withdrawn
Also available via

http://www.ich.org/cache/compo/276-254-1.html

Slide 10
 Remember that these have been adopted in the

European Union, the United States, and Japan
 Technically ICH guidelines apply only to new
APIs & products made from them. But most
regulators give ICH guidelines considerable
weight when deciding requirements for non-new
APIs.

Slide 11
WHO stability guidelines - 1
 “Guidelines for stability testing of pharmaceutical
products containing well established drug substances
in conventional dosage forms”
WHO (1996)
Available via
http://whqlibdoc.who.int/trs/WHO_TRS_863_(p1-p98).
pdf
Note:
– Applies to ‘Well established drug substances’
– Applies to ‘Conventional dosage forms’
– These guidelines are under revision : See h
ttp://www.who.int/medicines/services/expertcommittees/pharmp
rep/41ec_meet/en/index.html
Slide 12
WHO stability guidelines - 2
 So what are the types of product to which WHO

guidelines (1996) do not apply?
– New chemical entities (NCEs)
• And possibly also new dosage forms of NCEs
– New combinations of actives
– Modified release dosage forms, including
• Slow release products
• Transdermal patches
• Modified release injections

Slide 13
Stability guidelines for WHO’s Prequalification
Program (PQP) - 1
 Stability testing: Section 3.11 of Guideline on

Submission of Documentation for Prequalification of
Multisource (Generic) Finished Pharmaceutical Products
(FPPs) Used in the Treatment of HIV/AIDS, Malaria &
Tuberculosis
– Available via http://mednet3.who.int/prequal/
– Are consistent with ICH guidelines
– There are extensive cross references to ICH guidelines
– Effectively the PQP text is a practical interpretation of ICH guidelines

Slide 14
Stability guidelines for WHO’s PQP - 2
“Extension of the WHO list of stable (not easily

degradable ARV) APIs”
PQP Guideline for generics;
Supplement 2; WHO (2006)
– Also available via http://mednet3.who.int/prequal/
– Read this carefully. It describes circumstances in which
a tentative 2-year shelf life may be allocated to certain
APIs & FPPs, subject to a number of strict conditions.

Slide 15
Stability report formats for WHO’s PQP
Annex 3: Model stability report of API

Annex 4: Model stability report of
capsules/tablets
Also available via http://mednet3.who.int/prequal/

Slide 16
Terminology –
adapted from ICH 2000 (1)
- Production batch:
- A batch manufactured at production scale using production
equipment & in a production facility as specified in the
registration application
- Pilot scale batch:

- A batch manufactured by a procedure “fully representative
of & simulating” full production scale. For tablets & capsules,
this means 100,000 units or 1/10th of production scale,
whichever is the larger

Slide 17
Terminology –
Re-test period: API

– The period of time for which the API remains within
specification when stored under the recommended conditions in
the proposed bulk storage container
– “After this period, the batch should be retested for compliance
with specifications & then used immediately” [if in compliance]

Slide 18
Terminology –
- Accelerated testing
- Studies designed to increase the rate of chemical degradation or physical
change by means of exaggerated storage conditions
- Intermediate testing
- Studies at 30degC/60%RH, intended for extrapolation to long term storage at
25degC [provided that 25degC is appropriate for the market in question]
- Stress testing
- API: Studies which elucidate intrinsic stab of API. Normally during development.
Normally more stressful than ‘accelerated’ testing.
- Finished product: Studies of effect of ‘severe’ conditions. Eg freeze/thaw cycling
for suspensions & emulsions, low humidity for aqueous liquids in moisture-
permeable containers.

Slide 19
Terminology –
 In-use stability testing:

– Establishes the “period of time during which a multidose
product can be used whilst retaining quality within an
accepted specification once the container is opened”
ICH Q1A (2000)
• For example:
– liquids that are reconstituted prior to use
– effervescent tablets in a moisture-proof container (eg Al screw-
cap tube)
– ophthalmic products (especially with respect to preservative
efficacy)

Slide 20
Terminology –
 Climatic zones:
– Partition of the world into three temperature classes based
on kinetic averaging of monthly temperatures, &
subdivision of the hottest class into predominantly wet or
predominantly dry
– Zones (Futscher & Schumacher 1972):
• I Temperate (21oC/45%RH)
• II Subtropical (25oC/60%RH with possibly high RH)
• III Hot & dry (30oC/35%RH)
• IV Hot & wet (30oC/70%RH)
– The temperatures above are kinetic averages

Slide 21
Extract of WHO Technical Report Series 937
Expert committee on specifications for pharmaceutical preparations (2006):
Quality assurance: Stability testing conditions
“The Secretariat reminded the Committee that the WHO guidelines had
been revised in the light of harmonization efforts in collaboration with
ICH. Subsequently focus had been placed within regional
harmonization initiatives on the recommendations for hot and humid
conditions (referred to as Zone IV). After extensive discussion the
Committee reached consensus that the WHO stability guidelines be
amended to reflect conditions for Zone IV as follows:
— Zone IVa (30 degrees Celsius and 65% relative humidity); and
— Zone IVb (30 degrees Celsius and 75% relative humidity).
It was agreed that each individual Member State within the former
Zone IV would need to indicate whether its territory should be
classified as Zone IVa or IVb.”

Slide 22
Consequently…
 Each nation within zone IV must now decide

whether to adopt a stability test condition of
– 30oC & 65%RH, or
– 30oC & 75%RH
 ASEAN nations & Brazil have adopted 30oC
& 75%RH

Slide 23
Terminology –
adapted from ICH Q1A 2000 (6)
Reduced study designs:

- Bracketing
- A design in which only the extremes are tested
at all time points, eg strength, pack size,
container fill
- Matrixing
- Designs in which a selected subset of samples
is tested, eg different strengths,
container/closure systems, batches
Slide 24
Example of a bracketing design
Strength 50mg 75mg 100mg

Batch 1 2 3 1 2 3 1 2 3
Container 15ml T T T T T T
size 100ml
500ml T T T T T T
T = Sample is tested

Slide 25
Example of a matrixing design
“One half reduction”
Time point (months) 0 3 6 9 12 18 24 36

Batch
T T T T T T
1
Batch
S1 T T T T T T
2
Batch
T T T T T
3
Strength
Batch
T T T T T
1
Batch
S2 T T T T T T
2
Batch
T T T T T
3
T = Sample is tested

Slide 26
When might bracketing & matrixing be appropriate?
(NB The following is not from ICH ! You must argue the case!)
- Container size?
- Batch size?
- Formulation of coating?
- With varying amounts of an excipient (eg starch, Mg

stearate)?

Slide 27
The risk associated with bracketing & matrixing
- If the results are not what you expected, you

may have insufficient to propose an
intermediate shelf life
- Would be risky to use bracketing & matrixing if

you did not have a good idea as to what the
product’s stability will be
- Consequently: Bracketing & matrixing designs

are used mainly for confirmatory studies

Slide 28
ICH minimum dataset at submission - 1
General case
Minimum time period covered
Study Storage condition
by data at submission
25oC ±2oC/60%RH ±5%RH or
Long term 12 months
30oC ±2oC/65%RH ±5%RH
Intermediate 30oC ±2oC/65%RH ±5%RH 6 months
Accelerated 40oC ±2oC/75%RH ±5%RH 6 months
ICH: “It is up to the applicant to decide whether long term stability studies are
performed at 25oC ±2oC/60%RH ±5%RH or 30oC ±2oC/65%RH
±5%RH.”
PQP: “Unless otherwise justified, 30oC ±2oC/65%RH ±5%RH is the real-time

condition for the prequalification project.”
And: The minimum time period for intermediate storage is 12 months.

Slide 29
ICH minimum dataset at submission - 2
 FPPs packaged in impermeable containers need not be

stored under controlled humidity conditions
 There are different minimum conditions for:

– Liquid products packaged in semi-permeable containers
[relating to potential loss of solvent]
– Products intended for storage in a refrigerator, freezer or deep-
freeze


Slide 30
Classes of degradation
- Chemical
- Physical
- Microbiological

Slide 31
Chemical degradation
Has been dealt with by Professor

York & Dr Mills

Slide 32
Physical degradation
(≡ physicochemical degradation)
- Physical properties can change too!

- Important attributes vary with dosage form
- Bottom line is relevance to quality, safety & efficacy
- Examples for liquid formulations:

- Appearance, colour, odour, pH, clarity (solutions) and freedom from visible particulate
contamination, size range of particulate contamination (large volume parenterals),
particle size distribution (suspensions), micelle size distribution (micellar solutions),
resuspendability (suspensions), viscosity, moisture content (powders for
reconstitution), phase separation (emulsions)
- See other examples at http://www.tga.gov.au/pmeds/argpmap14.pdf

Slide 33
Other forms of physical deterioration may include :
- Leaching
- Absorption (into container walls)
- Adsorption (on to container walls)
- Volatilisation (eg sertraline base, glyceryl trinitrate)
- Altered particle size distribution
- Loss of higher order molecular structure (normally
only for biological medicines)
- Denaturation
- Aggregation

Slide 34
Minimising physical deterioration
- Some examples:
- When prone to adsorption on to, or absorption into,
packaging materials, use resistant packaging
materials, such as good quality glass
- When prone to volatilisation:
- Use a non-volatile salt (if possible)
- Use packaging materials that are resistant to vapour transfer
- When prone to altered particle size in suspensions:
- Formulate a continuous phase in which the active is less soluble

Slide 35
Microbiological deterioration
 Proliferation of microbes in non-sterile products
 Consequences may include:

– Infection of the patient
– Formation of endotoxins (≡ pyrogens)
– Foul odour
- Formation of gas
- Change in colour
- Cloudiness
- Hydrolysis

Slide 36
Minimising microbiological deterioration of non-
sterile products
- Control the microbial load of API &

excipients
- Validate & monitor manufacturing
conditions
- Include antimicrobial preservatives in
formulations
- NB Normally only bacteriostatic & not bactericidal

Slide 37
Appropriate tests for stability studies - 1
- Normally test same attributes as for routine

QC
- May use other methodology for stability testing

(avoid for dissolution rate) but must be
validated
- Avoid changing methodology mid-study

(unless correcting a clear deficiency)

Slide 38
Appropriate tests for stability studies - 2
- Quantitate degradation products if possible, even if

the assay is specific for the API
- But can be difficult to quantitate impurities if there are no
reference standards & relative response factors are
unknown → semiquantitative estimates
- Regulatory authorities usually expect an approximate
mass balance
- Appropriate physical tests vary with dosage form.

- Remember to conduct preservative efficacy tests
too, in addition to assay of any antimicrobial
preservative

Slide 39
For all stability studies
 Validate the analytical methodology!

– See relevant guidelines, especially:
• Validation of analytical procedures: Terminology
– ICH Q2A 1994
• Validation of analytical procedures: Methodology
– ICH Q2B 1996
 Use stability-indicating assays

Slide 40
Dissolution rate
- Avoid using a method different to that in routine

QC
- Most regulatory authorities, including PQP, prefer

dissolution profiles rather than single time points
during stability testing. Better ability to detect
trends.

Slide 41
Frequency of testing during a stability study - ICH
 “For long term studies, frequency of testing should be sufficient

to establish the stability profile of the pharmaceutical product”
 “For products with a proposed shelf life of at least 12 months,

the frequency of testing in the long term storage condition
should normally be every 3 months over the first year, every 6
months over the second year, & annually thereafter throughout
the proposed shelf life.
 Other frequencies are suggested for accelerated &

intermediate storage conditions.
 ICH Q1A(R2) 2003

Slide 42
Some notes concerning reporting (1)
- It is rarely appropriate to cite only average results

- For the benefit of the manufacturer & the DRA
- Dissolution results on individual tablets (not only mean results)
- It’s certainly OK to cite mean & derived results as well
- Assay results should be reported as absolute values

- And not only as values normalised for initial results, ie % of initial
- Test methods must be recorded with the study report

- By the time that stability studies are conducted on finished product, is possible that
more than one method has been used

Slide 43
Some notes concerning reporting (2)
- Numerical results should be provided wherever possible

- Not just ‘complies’
- If results are below the limit of quantitation, they should be

reported as ‘below LQC’ or similar wording
- ‘Not detectable’ is acceptable provided it is defined & reasonable
- Results that are out of the ordinary should be discussed
- Product labelling should be consistent with stability data.

For example:
- Solvents for reconstitution
- Recommendations for mixing of injections with other injections

Slide 44
Evaluation / Interpretation of the results
So what’s the shelf life?

Slide 45
First point
The validity of an assigned shelf life
depends upon:
- The results of stability studies, &
- Whether the batches used in the stability
studies accurately model those to be
marketed, &
- Whether analytical methodology was
adequately validated

Slide 46
Assigning a shelf life
 Assigning a shelf life is easier if results are available:

- For the full duration of the proposed shelf life
- At the maximum recommended storage conditions
- For all formulations & manufacturing methods
- In exactly the packaging to be registered
- At all sites of manufacture of finished product & API
 If these conditions are not met, that’s when shelf life

assignment becomes difficult.
– There will be arguments between manufacturers &
registration/prequalification authorities
– There will be delays in approving the product

Slide 47
Statistical estimation of shelf life - 1
 “Where the data show so little degradation & so little variability

that it is apparent from looking at the data that the requested
shelf life will be granted, it is normally unnecessary to go
through the formal statistical analysis but only to provide a
justification for the omission”
 ICH 2003 & PQP 2005
In other words: If it is blindingly obvious that there is minimal

change in the parameter in question, is unnecessary to
conduct the numerical/statistical analysis.

Slide 48
 “An approach for analyzing data of a quantitative

attribute that is expected to change with time is to
determine the time at which the 95% one-sided
confidence interval for the mean curve intersects the
acceptance criterion”
 ICH Q1A(R2) 2003

Slide 49
Is there any degradation of any relevant product

characteristic?
• If no, then shelf life assignment is straightforward based on the labelled
storage conditions & the time for which testing has been conducted
• If yes (that is there is at least some degradation/change):
• Conduct a statistical analysis using a suitable software package
• Consider:
 Statistical pooling of results for multiple batches
 Estimation of time to degrade to expiry limits using a 95% confidence interval
• See the file concerning software packages
– NB I am not recommending any of these software packages!
– Conduct your own Internet search! Then evaluate cost against usefulness to
your company.

Slide 50
Superimposition of a 95% confidence interval on to the

regression line for stability data from Bolton 1984
NB This is an old graph & it describes a very unstable product

Slide 51
What are the limitations of this statistical
algorithm?
- It applies only to quantitative attributes

- Does not apply for example to colour tests, or to semiquantitative
comparisons such as TLC limit tests
- It may be unreliable for physical attributes

- Such as dissolution tests & discoloration
- Use your judgement! Look at the slope of the curve.

Does the change accelerate with time?

Slide 52
Estimation of shelf life
 “Any evaluation should consider not only the assay

but also the degradation products & other appropriate
attributes”
 ICH Q1A(R2) 2003
In other words: If evaluation of different (but relevant) attributes

leads to different conclusions as to shelf life, the shortest of
these shelf lives should be chosen.

Slide 53
Estimation of shelf life
 “Where appropriate, attention should be paid to

reviewing the adequacy of the mass balance &
different stability & degradation performance”
 ICH Q1A(R2) 2003
– In other words: If the loss of active is not of the same order

(=approximately the same) as formation of degradation
products, more investigation is needed.
– Note however that mass balance will always be
approximate; it is rarely exact.

Slide 54
Factors to be taken into account when assigning a
shelf life based on statistical analysis - 1
- Release limits
- Expiry limits
- Results of stability studies
- Is there any desired safety margin?

- This is largely a matter for the manufacturer/supplier

Slide 55
Factors to be taken into account when assigning a
shelf life based on statistical analysis - 2
 A batch may be released with a result anywhere

in range of release limits
 Consequently a prudent manufacturer will take

into account the lower limit of release when
estimating shelf life

Slide 56
Combining results for several
batches
Poolability

Slide 57
Poolability of multiple batches
 A statistical concept that allows the results for several

batches to be combined
 If we estimated stability based on results for individual
batches, we would have to select the shortest estimate
of shelf life
 Pooling usually leads to a longer shelf life as compared
with the results for one batch only
 But we must first test whether the batches can
legitimately be pooled
 Are the batches statistically homogenous?

Slide 58
Testing for poolability as described by Bolton 1997
Perform statistical
test for common slope
Significantly Not significantly

different different
Use separate slope Perform statistical test

& intercept for each for common intercept
batch
Significantly Not significantly

different different
Use common slope but Use common slope &

separate intercepts common intercept
Significance is on the basis of F tests (p>0.25) as modelled by Bolton 1997

Slide 59
Extrapolation beyond real-time data - 1
 “Limited extrapolation of the real time data from the long

term storage condition beyond the observed range to
extend the shelf life can be undertaken at approval time, if
justified. This justification should be based on what is
known about the mechanisms of degradation, the results of
testing under accelerated conditions, the goodness of fit of
any mathematical model, batch size, existence of
supporting stability data, etc. However, this extrapolation
assumes that the same degradation relationship will
continue to apply beyond the observed data.”
 ICH Q1A(R2) 2000

Slide 60
Extrapolation beyond real-time data - 2
 “If long term data are supported by results from

accelerated studies the retest period/shelf life
may be extended beyond the end of the long-
term studies. The proposed retest period or
shelf life can be up to twice, but should not be
more than 12 months beyond, the period
covered by long-term data”. ”
 PQP 2005

Slide 61
References
References in your CD may be useful:
- Regulatory guidelines
- Sources of climate-controlled cabinets
- Software for processing stability data

- Most include laboratory information management for the
data

Slide 62
Summary and conclusion
 Stability data submitted during the registration process

should confirm that all batches of the FPP will remain
of acceptable quality when stored in the marketing
container, at the most extreme storage conditions
permitted by container labelling & prescribing
information, for the duration of the shelf life
 Any subsequent variations (for example to site or
method of manufacture of the API or FPP) should be
shown not to reduce the shelf life as defined above

Slide 63

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Pharmaceutical Development

Training Workshop on Pharmaceutical Development

Stability testing of Finished

Training Workshop on Pharmaceutical Development

 Define the objectives of stability testing

 Outline the design & conduct of stability studies for finished

 Determine a shelf life based on study results

 Discuss what to include in reports of stability studies

Training Workshop on Pharmaceutical Development

 "…… to provide evidence on how the quality of a drug

ICH Q1A (2003)

Training Workshop on Pharmaceutical Development

 Site and method of manufacture

 Batch to batch variability

Training Workshop on Pharmaceutical Development

Training Workshop on Pharmaceutical Development

- The product maintains relevant quality

Training Workshop on Pharmaceutical Development

Training Workshop on Pharmaceutical Development

 Q1A(R2) Stability Testing of New Drug Substances

 Q1B Stability Testing : Photostability Testing of

 Q1C Stability Testing for New Dosage Forms

Training Workshop on Pharmaceutical Development

 Q1D Bracketing and Matrixing Designs for Stability

 Q1E Evaluation of Stability Data

 Q1F Stability Data Package for Registration

Also available via

Training Workshop on Pharmaceutical Development

 Remember that these have been adopted in the

Training Workshop on Pharmaceutical Development

 So what are the types of product to which WHO

Training Workshop on Pharmaceutical Development

 Stability testing: Section 3.11 of Guideline on

Training Workshop on Pharmaceutical Development

“Extension of the WHO list of stable (not easily

Training Workshop on Pharmaceutical Development

Annex 3: Model stability report of API

Training Workshop on Pharmaceutical Development

- Pilot scale batch:

Training Workshop on Pharmaceutical Development

Re-test period: API

Training Workshop on Pharmaceutical Development

Training Workshop on Pharmaceutical Development

 In-use stability testing:

Training Workshop on Pharmaceutical Development

Training Workshop on Pharmaceutical Development

Training Workshop on Pharmaceutical Development

 Each nation within zone IV must now decide

Training Workshop on Pharmaceutical Development

Reduced study designs:

Strength 50mg 75mg 100mg

Training Workshop on Pharmaceutical Development

Time point (months) 0 3 6 9 12 18 24 36

Training Workshop on Pharmaceutical Development

- With varying amounts of an excipient (eg starch, Mg

Training Workshop on Pharmaceutical Development

- If the results are not what you expected, you

- Would be risky to use bracketing & matrixing if

- Consequently: Bracketing & matrixing designs

Training Workshop on Pharmaceutical Development

PQP: “Unless otherwise justified, 30oC ±2oC/65%RH ±5%RH is the real-time

Training Workshop on Pharmaceutical Development