Stability Principles and Case Studies:
Active Pharmaceutical Ingredient (API)
and
Finished Pharmaceutical Product
(FPP)
Gabriel K. Kaddu
WHO Prequalification of Medicines Programme
Assessment training, Copenhagen
May 2014
1
Overview
• Purpose of stability
• Section 2.3.S.7.1(a)/ 2.3.P.8.1(a): Stress Testing
• Section 2.3.S.7.2/ 2.3.P.8.2: Post approval Stability
commitments
• Storage conditions
• Section 2.3.S.7.3/ 2.3.P.8.3: Stability Data
• Stability data
• Other stability studies
• Assessment Tips
2
Purpose of stability
• the purpose of stability testing is to: “provide evidence of
how the quality of an API or FPP varies with time under
the influence of a variety of environmental factors such
as temperature, humidity and light.”
• The stability programme also includes the study of
product related factors that influence the quality of the
API or FPP, for example, interaction of API with
excipients, container-closure systems and packaging
materials.
3
API- 2.3.S.7.1 (a):
Summary of stress testing
• Stress testing: can help identify the likely degradation
products which, in turn, can help to
• establish the degradation pathways and the intrinsic
stability of the molecule
• and validate the stability-indicating power of the
analytical procedures used.
• Stress testing may be carried out on a single batch of the
API
4
API- 2.3.S.7.1 (a):
Summary of stress testing
• The objective of stress testing is not to completely
degrade the API but to cause degradation to occur to a
small extent, typically 10–30% loss of API
• by assay when compared with non-degraded API. This
target is chosen so that some degradation occurs, but
not enough to generate secondary products.
• For this reason the conditions and duration may need to
be varied when the API is especially susceptible to a
particular stress factor.
• In the total absence of degradation products after 10
days the API is considered stable under the particular
stress condition.
5
API- 2.3.S.7.1 (a): Summary of stress
testing
Stress
conditions
Heat
Humidity
Oxidation
Photolysis
Acid
Base
Other
6
Treatment
Results
FPP- Section 2.3.P.8.1(a):
Stress testing
• Formal stress testing for the FPP is not required, except:
 Light stressing should be shown for the FPP (ICH
Q1B)
 If the API was not demonstrated to be light stable,
and
 If the packaging has not been demonstrated to be
light protective
 Stress testing is required as part of method validation,
to show the assay and/or related compounds method
is stability-indicating.
7
Generic Guideline
“The quality guideline (TRS 970 Annex 4,
Section P.8.1) states, “If “protect from light” is
stated in one of the officially recognized
pharmacopoeias for the API or FPP, it is
sufficient to state “protect from light” on
labelling, in lieu of photostability studies when
the container-closure system is shown to
be light protective.”
8
Light stress testing or
photo-protective packaging
We can look at:
 “Protect from light” warnings in monographs
 “Protect from light” in APIMF
 Photo stress testing
 Packaging
9
FPP
• photostability testing should be conducted on at least
one primary batch of the FPP if appropriate.
• If “protect from light” is stated in one of the officially
recognized pharmacopoeias for the API or FPP it is
sufficient to state “protect from light” on labelling, in lieu
of photostability studies, when the container-closure
system is shown to be light protective.
10
Light stressing/Light transmission
What is needed:
Note that photostability testing according to ICH Q1B is
“required”, however we use a pragmatic approach.
a) Either photostability demonstration (progression of API,
FPP exposed, FPP in package) or
b) light transmission data.
photostability testing should be conducted on at least one
primary batch of the FPP if appropriate.
11
Conclusion: Light stressing
• Product should be shown to be light stable by
photostability studies
a) showing the dosage form or dosage form in
packaging is photostable.
b) By light transmission studies showing adequate
protection of the packaging.
c) for blisters, which are not light protective, store blisters
in carton (must be clear in QIS and on labels)
• If product is not light stable; label should state that
protect from light and container should be light protective
– light transmission tests should be carried out on the
container closure system
12
Storage Conditions
Climatic Zones
• Zone I: 21ºC/45% RH
• Zone II: 25ºC/60% RH (subtropical)
• Zone III: 30ºC/35% RH(hot/ dry)
• Zone IVA: 30ºC/65% RH (hot/ humid)
• Zone IVB: 30ºC/75% RH (hot/very humid)
Long term stability studies should cover all climatic zones if
possible
13
3.2.S.7.1(b)/ 3.2.P.8.1(b):
Accelerated and Long term testing
• Stability data must demonstrate stability of the medicinal
product throughout its intended shelf-life under the
climatic conditions prevalent in the target countries.
• Effective as of September 2011, the required long-term
storage conditions for the WHO Prequalification of
Medicines Programme are 30ºC ± 2º C/75% ± 5% RH.
The use of alternative long-term conditions should be
justified and should be supported with appropriate
evidence.
14
When the API or FPP stability studies
were not conducted at PQ conditions:
• The required long-term stability condition within the WHO
Prequalification programme is 30ºC/75%RH for both API
and FPP (Note: 30±2°C/ 65±5% RH is also
acceptable for API), unless documented evidence can be
provided that storage under these conditions is not
possible due to the inherent chemical instability of the
API. In light of this, please provide long-term stability
data for your API at 30C/75%RH or provide documented
evidence that such storage conditions are inappropriate.
15
When the API or FPP stability studies
were not conducted at PQ conditions:
API
• If long-term stability data at 30±2°C/ 65±5% RH or
30ºC/75%RH is not available for API, please commit to
generating such data on the next three production scale
batches of XXXXXXXX; provide a signed detailed
protocol describing this stability programme; and commit
to providing an amendment to alter the recommended
storage conditions and retest period once 24 months
stability data has been generated.
16
FPP
• In cases where the delay in accepting the dossier in
order to obtain the stability data at 30ºC/75%RH is
unacceptable:
• The required long-term stability condition within the WHO
Prequalification programme is 30ºC/75%RH, unless
documented evidence can be provided that storage
under these conditions is not possible due to the inherent
instability of the product. In light of this, please provide
long-term stability data for your product at 30C/75%RH
or provide documented evidence that such storage
conditions are inappropriate.
17
FPP
• If long-term stability data at 30ºC/75%RH is not
available, you are required to commit to initiating studies
at 30ºC/75%RH on the required number of primary
batches; provide a signed detailed protocol describing
the stability programme including a commitment for the
date of initiation of studies, no more than 60 days from
today’s date.
18
Storage directions - temperature
• Sometimes the applicant wants “store below 25°C”
when they have demonstrated stability at 30°C.
• Example comment to applicant: As of September 2011
we require stability data at 30C, and when this is
demonstrated “store below 30C” is encouraged on
labelling. Additionally, you should be aware that
procurement agencies prefer products labeled, “store
below 30C” as it indicates that stability was
demonstrated at 30C. You are requested to reconsider
the decision to label the product, “store below 25C”.
We suggest and can explain, we cannot insist.
19
3.2.S.7.1(b)/ 3.2.P.8.1(b):
Condition
Storage
Relative humidity
Minimum
time
Accelerated
and
Long
term
testing
temperature (ºC)
(%)
period
(months)
Accelerated
40 ± 2
75 ± 5
6
Long-term
30 ± 2
75 ± 5
(for both API and
FPP)
6
65 ± 5
(for API)
20
Exceptions: Reproductive Health and
2nd line TB drugs 1
•
21
the requirement for stability at the time of submission
only, may be reduced to;
1) no less than 3 months accelerated,
2) plus 3 months long-term data,
for not less than two primary batches of at least pilot
scale or in the case of an uncomplicated1 FPP (e.g.
immediate-release solid FPPs (with noted exceptions),
non-sterile solutions), not less than one batch of at least
pilot scale and a second batch which may be smaller
(e.g. for solid oral dosage forms, 25 000 or 50 000
tablets or capsules) of each proposed strength of the
FPP.
Exceptions: Reproductive Health and
2nd line TB drugs 2
22
• One of the primary batches (also called exhibit, preapproval, registration, submission, or test batches)
should be the batch that was used for bioequivalence
studies.
• All prequalification requirements for final acceptability of
the dossier remain in effect, without exception;
1) the submission of updated stability data during the
assessment period as it becomes available, and
2) a commitment to provide:
a) stability data on three production batches, and
b) process validation of three consecutive production
batches, to be completed prior to marketing.
3.2.S.7.1(b)/ 3.2.P.8.1(b):
Accelerated and Long term testing
• Other storage conditions are outlined in the WHO
stability guidelines:
 for FPPs packaged in impermeable and semipermeable containers and
 those intended for storage in a refrigerator and in a
freezer.
 FPPs intended for storage below −20°C should be
treated on a case-by-case basis.
 Weight loss from plastic containers should be
reported over the shelf-life (Liquids only).
23
Stability of aqueous liquids
Aqueous Liquids in semi-permeable containers – ICH Q1
and TRS953: long term studies should be at 25°C/40%RH
or (for PQ) 30°C/35%RH plus 40°C/25%RH
•Q1A: “Aqueous-based products packaged in semipermeable containers should be evaluated for potential
water loss in addition to physical, chemical, biological, and
microbiological stability…Ultimately, it should be
demonstrated that aqueous-based drug products stored in
semi-permeable containers can withstand low relative
humidity environments. ”
Container closure systems 1
Semi-permeable (ICH and TRS 953):
•Containers that allow the passage of solvent, usually
water, while preventing solute loss […]
•Examples of semi-permeable containers include plastic
bags and semi-rigid, low-density polyethylene (LDPE)
pouches for large volume parenterals (LVPs), and LDPE
ampoules, bottles, and vials.
•HDPE bottles are considered semi-permeable for storing
liquids.
Container closure systems 2
Impermeable
•Containers that provide a permanent barrier to the
passage of gases or solvents, e.g. sealed aluminium
tubes for semisolids, sealed glass ampoules for solutions
(ICH/TRS 953) and (TRS 953 only) aluminium/aluminium
blisters for solid dosage forms. (Be careful of Al/Al, it
depends on the sealing.)
Container closure systems 3
• TRS 953: “Sensitivity to moisture or potential for solvent
loss is not a concern for FPPs (for liquids) 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 relative
humidity condition.
• Note: This does not apply to AL/ Al blisters. For Al-Al
blisters, humidity in stability studies is just as important
as for bottles. It is just that moisture permeability does
not have to be tested for the package.
27
Section 3.2.S.7.2/ 3.2.P.8.2 Post-approval
stability commitment
• 2.3.P.8.2(a): Primary stability study commitment
• 2.3.P.8.2(b): Commitment stability studies
• 2.3.P.8.2(c): Ongoing stability studies
Parameter
Storage conditions(s) (ºC, %RH)
Batch number(s)/ Batch Size(s)
Tests and acceptance criteria:
Description
Assay etc
Testing frequency
Container closure system
28
Details
Section 3.2.S.7.2/ 3.2.P.8.2:
Post-approval stability protocol
• number of batch(es) and different batch sizes, if
applicable;
• relevant physical, chemical, microbiological and
biological test methods;
• acceptance criteria;
• reference to test methods;
• description of the container-closure system(s);
• testing frequency;
• description of the conditions of storage
29
Information on stability studies
•
•
•
•
•
•
•
30
– storage conditions;
– strength;
– batch number, including the API batch number(s) and
manufacturer(s);
– batch size;
– completed (and proposed) test intervals.
– container-closure system including orientation (e.g.
erect, inverted, on-side) where applicable; important for
liquids and semi-solids (e.g. erect, inverted, on-side):
This is to study the possible interaction of the container
closure system (the container and the closure) with the
product.
Section 3.2.S.7.3/ 3.2.P.8.3:
Stability data
• Results of the stability studies should be presented in an
appropriate format :
 tabular,
 graphical,
 Narrative
• Summary of analytical methods
 Information on the analytical procedures used to
generate the data and validation of these procedures
should be included.
31
Stability reports
• General information: name, manufacturing sites, date of
manufacturing; batch number, batch size.
• Container closure system, tests and acceptance criteria ,
test frequency, storage conditions—should in line with
the protocol
• Evaluation of stability data-- any significant change? Out
of specification? out of trend?
• Conclusions
– retest period for drug substance, or shelf life, if
applicable
– storage condition
32
API: Retest period
• A retest period should be derived from the stability
information and should be displayed on the container label.
• After this retest period a batch of API destined for use in the
manufacture of an FPP could be retested and then, if in
compliance with the specification, could be used immediately
(e.g. within 30 days). If retested and found compliant, the
batch does not receive an additional period corresponding to
the time established for the retest period. However, an API
batch can be retested multiple times and a different portion of
the batch used after each retest, as long as it continues to
comply with the specification. For APIs known to be labile
(e.g. certain antibiotics) it is more appropriate to establish a
shelf-life than a retest period.
33
Change in specifications
A change in specifications is a stability
issue.
Stability issue – specifications have
changed
• Often during assessment specs are revised (by request
usually) but there is no attention paid to whether stability
data supports the change.
• [This is another reason why it is so important to compare
previous specs to the revised version provided.]
• It is not sufficient to accept only a commitment for
results for the new specification.
• When we accept a shelf-life we are saying we are
satisfied that the specifications will be met based on
data we have assessed.
Stability issue – specifications have
changed
If the revised limits can be assessed using current
data, just ensure the new limits are met by most recent
stability data.
•Example tightened impurity limits: we can usually tell
whether the new limits have been met by reviewing the
available data
Imp A: up to 0.2% reported; meets new limit of NMT 0.1%
Exception in this case is TLC: semi-quantitative results
were provided:
Imp A: < 0.2% reported; can’t tell if new limit (0.1%) is met
Stability issue – specifications have
changed
The revised limits may require new testing/reporting,
such as inclusion of a limit for a new impurity or a different
dissolution timepoint. In these cases, the available data is
insufficient:
1. If studies are completed: Request available data on
retained samples if not far beyond expiry, or available new
studies
2. If studies are ongoing: Request that data at subsequent
stations include the revised limits.
Stability-indicating parameters
• Stability-indicating parameters must be understood for
the API and FPP.
• API: any parameter susceptible to change (appearance,
assay, impurities*, others specific to the API e.g.
polymorphism if necessary)
• Why all specified impurities, and not just degradation
products for the API? The way to determine if an impurity
is also a degradant is to do the stability and monitor
known impurities. A process impurity could also turn out
to be a degradant. The degradants for an API by one
manufacturing process may differ from that of another,
for example due to the presence of trace metals or other
reagents.
Stability-indicating parameters
FPP:
Physical (description, moisture, quality parameters (DT,
dissolution));
• Moisture is particularly important for solid orals in blisters
and strips, and moisture-sensitive products in bottles.
Chemical (assay, degradants, preservatives);
Efficacy of additives
Container/closure interactions, when applicable (e.g.
liquid in plastic);
Evaluation and Extrapolation of
results
• if significant change was not observed within 6 months at
accelerated condition and the data show little or no
variability, the proposed shelf-life could be up to twice
the period covered by the long-term data, but should not
exceed the long-term data by more than 12 months
• The proposed storage statement and shelf-life (and inuse storage conditions and in-use period, if applicable)
for the FPP should be provided. The recommended
labelling statements for use based on the stability
studies, are provided in the WHO stability guidelines
40
Provisional shelf-lives 1
• Ideally, these would not exist. As long as there are
significant question(s) and the data did not cover the
proposed shelf-life, updated data should be
requested/provided.
• Example problem: 12 mo data provided in blisters and
then the study was discontinued. A provisional 24 mo
shelf-life was accepted. Is this okay?
• No. You can’t extrapolate based on data for batches
when the study on these batches will not be continued
over the extrapolated period.
Provisional shelf-lives 2
Never accept extrapolation for cancelled studies. ICH
Q1E:
“a retest period or shelf life granted on the basis of
extrapolation should always be verified by additional longterm stability data as soon as these data become
available.”
WHY? 1) we don’t know why the studies were cancelled.
2) we don’t have the normal assurance of the “primary
stability commitment”, and 3) if they cancelled studies (in
the above case they claim because of low market
potential), the odds of them starting a new study are slim.
This is very risky and against all practices.
Updated stability data and
extrapolation – what NOT to say
“Please provide update stability data. In order to support of
24 months shelf life of the product, long term stability data
up to at least 12 months should be provided, with
commitment to continue long term testing for a period of
time sufficient to cover the whole proposed shelf life.”
The above suggests that we will accept 12 months data,
and extrapolate on this, even if longer data is available.
What TO say:
“In order to support the proposed shelf-life, you are
requested to provide available updated stability data.”
Extrapolation
1. Ask for the available updated stability data each time
comments are going out.
2. Don’t imply that extrapolation is a guarantee as in the
example question. It depends on the actual data
provided.
3. Don’t offer extrapolation unless it has specifically been
proposed by the applicant.
2.3.S.7.1(b)/ 2.3.P.8.1(b):
Summary of accelerated and long
term testing
Storage
conditions
(ºC, % RH)
Strength and
Batch number
Batch
size
Container
closure
system
• Summary of stability results observed
Test
Description
Moisture
Impurities
Assay
45
Results
Completed (and
proposed) test
intervals
Other stability studies
Hold time studies: validate holding times - how long an
intermediate can be stored, including bulk product prior to
final packaging
In-use studies: studies to show that normal in-use of the
product will not result in significant changes in the product
Transport studies: studies to show a bulk product will still
meet the release limits after transportation to the packaging
site
Each of these studies have their own requirements.
46
Hold time Studies 1
Summary of acceptable hold times
A maximum processing time of one month (30 days) is
acceptable without validation. (industry standard)
Any hold time for an intermediate or the bulk product >30 days
must be supported by stability studies.
In addition, cumulative hold times should not exceed 90 days, or
additional supporting data is required.
47
Hold time studies 2
These are a type of stability study to determine hold times
for example for blend, cores and final coated tablets in bulk.
Necessary when hold time > 30 days or there are multiple
hold times (e.g. 30+30+30+30).
•All stability-indicating parameters should be included in the
studies.
•The applied limits are important. Release limits should be
applied to final tablets, not just shelf-life.
48
Hold time studies 3
Beware of even short hold times for liquid intermediates.
Example comment:
• The API-loaded suspension is allowed to be stored for
three days before being further used for processing. The
suspension contains HPMC and lactose, both of which
could promote microbial growth. Please provide the
supporting data for microbial stability of the
suspension and the chemical stability of the API for
the proposed waiting period of three days during
processing.
49
Hold time studies 4
Common issue: a number of intermediates have hold
times
Beware of cumulative hold times, even if separately
validated
The date of production of a batch is defined as the date that
the first step is performed involving combining the API with
other excipients.
Even if appropriate hold studies have been provided to
support hold times, the hold times still may be
unacceptable.
50
Hold time studies 5
Recent example (controlled release (CR) tablet):
Blend
25 days
Compressed tablets
30 days
Seal coated tablets
5 days
CR coated tablets
30 days
Laser drilled tablets
30 days
Bulk tablets
1 months
Total hold time > 5 months before packaging! Shelf-life is
only 24 months. This should be questioned! E.g. Flag
this if >3 months total
51
Hold time studies 6
Comment out:
You have indicated cumulative hold times prior to the
stage of packaging of the product that add to over 5
months. You are reminded that the start of shelf-life is
defined as the time of first mixing of an excipient with the
API. You are requested to significantly reduce the
hold times so that the maximum processing time will
be kept at a reasonable duration (e.g. 30 days) or
provide additional evidence that a product subject to
the cumulative effect of the largest hold times would
still meet release specifications as well as shelf-life
specifications over the remaining shelf-life.
52
In-use studies 1
TRS 970 Annex 4 states: Any in-use period and
associated storage conditions should be justified with
experimental data, for example, after opening,
reconstitution and/or dilution of any sterile and/or multidose
products or after first opening of FPPs packed in bulk
multidose containers (e.g. bottles of 1000s*). If applicable,
the in-use period and storage conditions should be stated
in the product information.
*only for rifampicin containing products and highly
hygroscopic products.
In use period of 28 days generally accepted without
data (most products).
53
In-use studies 2
Standard comment out:
It is noted that a two month in-use period is claimed for the
product. As outlined in the quality guideline (TRS 970
Annex 4, P.8.1 p. 184), any in-use period and associated
storage conditions should be justified with experimental
data. A minimum of two batches of at least pilot scale*
should be subjected to the test. At least one of the
batches should be chosen towards the end of its shelflife.
* May use lesser requirement for uncomplicated FPPs
54
In-use studies 3
As far as possible the test should be designed to simulate
the use of the product in practice (i.e. the same bottle
opened at each interval), taking into consideration the
filling volume of the container. At intervals comparable to
those that occur in practice, appropriate quantities should
be removed by the withdrawal methods normally used and
described in the product literature.
In the case where the package size is inadequate for the
full study: One unit (tablet or capsule) may be withdrawn
and then replaced.
55
In-use studies 4
• Rather than just opening the bottle, the protocol should
specify that at least one capsule is picked out each time
it is opened, and then it may be immediately returned to
the bottle for future analysis. This is to ensure that air
moves in the bottle as it is expected to during normal
use.
56
Transport studies 1
It is transportation of bulk product that requires transport
studies. Transportation of packaged product is not
normally required (may be requested in special cases).
If there are stability issues with the FPP, then study results
may be requested.
57
Transport studies 2
If there are no stability issues with the FPP, we do not
pursue study results. Instead a protocol is sufficient,
including:
 at least one batch of at least pilot scale;
 confirmation of whether the product will be shipped in a
controlled environment, with or without transportation
logging devices; and
 If not a controlled environment, assessment of
environmental conditions to which the product will be
exposed during transportation, and studies to support the
stability of the product in the bulk package at the extremes
of the likely conditions.
58
Tips for Assessment of Stability
Studies
CASE STUDY ON STABILITY STUDIES
Assessment Tips for stability 1
1. Has the applicant provided the stability protocol? Check
the conditions used in the stability studies
2. Has the applicant submitted accelerated stability
studies? 40±2°C/ 75±5% RH.
3. Has the applicant submitted long term stability studies?
30±2°C/ 75±5% RH for API and FPP (30±2°C/
65±5% RH is also acceptable for API) except for
justified cases.
60
Assessment Tips for stability 2
4. Check the period of the stability studies submitted:
atleast 6 months for both accelerated stability studies
and long term stability studies. Exceptions: RH products
and 2nd line TB drugs
5. Check the number of batches used in the stability
studies
6. Check the batch size of the batches used in the stability
studies. Are they acceptable: atleast 2 batches of pilot
scale or for an uncomplicated FPP, one of pilot scale
and second batch which may be smaller
61
Assessment Tips for stability 3
7. Check the type of the container closure system
including the type of the material of the cap used in the
stability studies: What is the type of packaging type
used including the type of cap, if applicable? Is it the
same as that declared in section 2.3.P.7?
8. Check the conditions used in the stability studies
9. Check the period of the stability studies submitted:
atleast 6 months for both accelerated stability studies
and long term stability studies. Exceptions: RH products
and 2nd line TB drugs
62
Assessment Tips for stability 4
10.Are all the stability indicating tests included?
11.Check the shelf life specifications against the
specifications used in the stability studies.
12.Check the results for each parameter at each test
station to confirm whether the results are all within the
limits (specifications). No failured
13.Is there any significant change observed in the stability
study results?
14.Summarize the trends for each parameter.
63
Assessment Tips for stability 5
15.Is there mass balance in the stability study results?
16.Do the stability studies submitted support the proposed
shelf life?
17.Do the stability studies support the proposed storage
condition? Does the compendia state any special
storage condition for the product?
The storage condition should include the provisions
stated in the compendia. The container closure system
should provide the necessary protection.
64
Assessment Tips for stability 6
Stability Commitments
18.Has the applicant submitted written and signed stability
study commitments (primary stability study commitment,
commitment stability study commitments and ongoing
stability study commitments)?
19.Check the batches stated under the primary stability
commitment: primary batches
20.Check the batches stated under the commitment
stability studies: first three consecutive commercial
batches.
21.Check the batches stated under the ongoing stability
study commitment: atleast one batch per year
65
References
• TRS_970- Annex 4 Generic Guideline
• QA Talks by L. Paleshnuik, Lead Quality Assessor PQP.
• Presentation- EAC Joint Session July 2013: Assessment
part XIV section P.8, L. Paleshnuik, Lead Quality
Assessor PQP.
• Presentation- EAC Joint Session July 2013: Process of
Assessment – API areas S.5, S.6, S.7, Hua Yin
• ICH Q1A, Q1B, Q1D, Q1E, Q2,
• WHO Technical Report Series, No. 953, Annex 2
66
Thank you
67