Stability Testing: Hua Yin

Stability testing
Hua YIN
1|
CPH training | May 2016
Stability –purpose
 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
2|
Stability –purpose
 Understand the molecule
 Select packaging
 Establish a retest period (API) or shelf-life & storage conditions
 Establish shelf life acceptance criteria of Specification
 Validate analytical methods
3|
References
 Generics Guideline (TRS 970 annex 4, section 3.2.S.7 and 3.2.P.8)
 Stability Testing of APIs and FPPs -- WHO Stability Guide in TRS953
(2009) Annex 2:
 ICH Q1(A, B, C, D and E)
 FDC guideline-- TRS 929 Annex 5 (appendix 3, Table A.1)
For PQTm, when there are contradictions, the Generic guideline prevails
 Lynda Paleshnuik. Annual Prequalification Assessment Training.
Copenhagen, 2010 & 2015
4|
Overview
 Stress testing (photostability)

 Accelerate, intermediate and long term stability studies
 Evaluation of the stability data
 Summarizing the stability data
 Trends, Significant changes, Out of specification results (OoS)
 Extrapolation
 Examples
5|
Stress Studies
Stability testing under conditions exceeding those used for accelerated

testing. Used to:
 establish the inherent stability characteristics of the molecule
 establish the degradation pathways
 identify the likely degradation products
 validate the stability indication power of the analytical methods
 formulation development, manufacturing process development
6|
Stress testing
 When available, it is acceptable to provide relevant data published in the

scientific literature to support the identified degradation pathways and
degradation products. For example,
If “protect from light” is stated in one of the officially recognized
pharmacopoeia, we can assume it is not photostable. Photostability data
may not be required if declare “protect from light”, and the container
closure system is shown to be light protective.
 When no data are available, stress testing should be performed.
7|
Stress testing
 No detailed stress testing strategy in Guidelines, except for

photostability (ICH Q1B)
experimental conditions and duration may need to be varied depending

on the nature of the drug substance
 Generic guideline refers to FDC guideline appendix 3, table A.1 (TRS

929 Annex 5) -- as examples
8|
API stability
Stress testing – Typical Stress conditions
9|
Stress Studies
 How much stressing is enough ?

 10-30% loss of API assay (FDC guideline, as well as Generic
guideline)
 between 5% to 20% degradation (some literature)
 approximately 10 % degradation is optimal for method validation (e.g.
shelf life assay limit 90.0%-110.0% of label claim)
 balance between "purposeful degradation" and irrelevant artifacts (e.g.,

secondary degradation products).
 degradation products not formed during accelerated or long-term stability

studies--need not always to be examined
10 |
Stress studies:
Approach for Assessment: DO
 Check if data is provided, either generated by
supplier/applicant or from literature references
 Check compendial statement, e.g “protect from light”.
 Check if conditions are adequate
 Check the extent of degradation

 ≈10% → adequate degradation
 little or no degradants : verify if conditions are "harsh" enough. If
yes, the API is considered stable.
 Conclude on the degradation pathways, stability nature of the API
11 |
Stress studies:
Approach for Assessment : DON’T
 spend excessive time with degradants generated in stress studies if they

are not formed in practice.
 The impurities/degradants that must be closely investigated are those

appearing when stored at long-term and accelerated conditions at greater
than (or approaching) the identification threshold (the limit of individual
unknowns, 0.1%).
12 |
Photostability Studies
 Photostability Studies should be conducted on at least one primary batch;

see ICHQ1B. Test progressively:
API
Exposed
FPP
FPP in
package
If any stage is photostable, no need to continue, e.g.:
if API shown photostable, then FPP testing is not necessary
13 |
Photostability Studies
 Either photostability should be demonstrated or light protection of packaging

demonstrated (light transmission data, e.g. USP <661>)
 A light sensitive product should be provided in light protective packaging. Be

careful to PVC, PVC/PVdC, PVC/PE/PVdC blisters. A opaque carton should
be included in the packaging description if necessary with a statement such
as, “Store tablets in blisters in the provided carton”.
14 |
Overview

 Extrapolation
 Examples
15 |
Stability protocol
 Number of batch(es) and batch sizes
 Container closure system (s)
 Conditions of storage
 Testing frequency
 Tests and acceptance criteria (reference to test methods)
16 |
Selection of Batches (PQTm)
 A) a retest period for an API: 3 API batches, at least pilot scale

 B) a shelf-life for the FPP:
 2 batches of at least pilot scale, OR，
 Uncomplicated products* – 1 batch of at least pilot scale + 1 batch which
may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets
or capsules) **
* Uncomplicated FPPs:
e.g. immediate-release solid FPPs (with noted exceptions), non-sterile
solutions
** the smaller batch should be representative to the biobatch
17 |
Container closure system (s)
 Should be the container proposed for storage/distribution including any

functional secondary packaging.
 Each strength and container type, pack size should be studied unless
bracketing/matrixing is applied.
 The storage orientation of the product, i.e. upright versus inverted, may
need to be included in a protocol when contact of the product with the
closure system may be expected to affect the stability of the products
contained.
Generally only a consideration for liquids and semi-solids.
18 |
Storage Conditions
Climatic Zones
 Zone I: 21°C/45% RH
 Zone II: 25°C/60% RH (subtropical)
 Zone III: 30°C/35% RH (hot/ dry)
 Zone IVA: 30°C/65% RH (hot/ humid)
 Zone IVB: 30°C/75% RH (hot/ very humid)
PQTm:
Long term stability studies should cover all climatic zones if possible, i.e
30°C± 2°C/75% ± 5% RH
Accelerated stability studies: 40°C± 2°C/75% ± 5% RH
* See ICH Q1 for conditions of storage in a refrigerator or a freezer
19 |
Testing Frequency
Accelerated : Minimum three points including t0 and tfinal, eg 0, 3, 6.

Long term :0, 3, 6, 12, 18, 24, 36
Intermediate : Four points including t0 and tfinal, eg 0, 6, 9, 12.
For PQTm, when long tem condition is Zone IV, there is no intermediate
condition
20 |
Minimum data requirements at time of submission
Storage temperature Relative humidity (%) Minimum time period

(ºC) (months) **
Accelerated 40±2 75±5 6
Intermediate * * *
Long-term 30±2 65±5 (API only) or 6

75±5 (API and FPP)
* Where long-term conditions are 30ºC±2ºC/65%±5%RH or 30ºC±2ºC/75%±5%RH, there

is no intermediate condition.
** for 2nd line TB and RH products, 3 months data at time of submission
21 |
Stability-indicating quality parameters
Monitor parameters susceptible to change:
 Physical: description, moisture;
 Chemical: assay, degradants;
 Performance tests: e.g. dissolution, disintegration (e.g. dispersible tablets)
 Efficacy of additives: Preservative content;
 Microbiological testing
Other tests for specific dosage forms, e.g. pH, clarity, particulate matter (for
solutions), fineness of dispersion (for dispersible tablets), sterility (for
parenterals), reconstitution time for powders
22 |
Non Stability-indicating quality parameters
Unlikely to change during storage:
 Identity
 Content uniformity
 Diameter/thickness
 Residual solvents
 Average weight
23 |
What are expected in the stability reports?
 General information: Product name, manufacturing sites, date of
manufacturing; batch number, batch size, strength, container/clourse (seals,
desiccants should be identified)
 Stability data in tables or graphs or both
 Evaluation
– Justify parameters tested (OoS, OoT discussion)
– Statistical analysis, if necessary
 Conclusions
– Proposed retest period or shelf-Life
– Proposed storage condition
24 |
Overview

 Extrapolation
 Examples
25 |
Evaluation of Stability Data
 Review the protocol and report, confirm the number of batches, batch
size, packaging, storage conditions, test frequencies, specification.
 Review the stability results (details follow)
Notes: Stability of the FPP is product-dependent, not solely due to the API
stability. Proceed with caution.
26 |
 Quality Overall Summary - Product Dossier (QOS-PD) 2.3.S.7 & 2.3.P.8

P. 8 Summary of accelerated and long-term testing parameters (e.g. studies conducted):
Storage conditions Strength and Batch size Container closure Completed (and
(◦C, % RH) batch number system proposed) test
intervals
 Use the mock dossier for example
27 |
 Quality Overall Summary - Product Dossier (QOS-PD) 2.3.S.7 & 2.3.P.8

P. 8 Summary of accelerated and long-term testing parameters (mock dossier P.8):
Storage conditions Strength and batch Batch size Container closure Completed (and
(◦C, % RH) number system proposed) test intervals
40°C±2°C/75%±5%RH X95910 100,000 tablets Completed – Initial, 1M, 2M,

X05172 100,000 tablets Blister strip of 2 tabs 3M and 6M
X85110 (Biostudy batch) 150,000 tablets Proposed – NA
30°C±2°C/75%±5%RH X95910 100,000 tablets Blister strip of 2 tabs Completed - Initial, 3M, 6M,
X05172 100,000 tablets 9M, 12M, 18M and 24 M
Proposed – 36M and 48M
25°C±2°C/60%±5%RH X85110 (Biostudy batch) 150,000 tablets Blister strip of 2 tabs Completed - Initial, 12Week,
6M, 9M, 12M, 18M, 24M
Date of mfg: X95910- Nov 2009, X05172 –Dec 2009, X85110 - Mar 2008
28 |
 Summary of the stability results observed for the above accelerated and long-term
studies:
Test Results
Description
Moisture
Impurities
Assay
Dissolution
etc.
29 |
Summary of the stability results
Example: 40°C±2°C/75%±5%RH, 6 Months. X95910, X05172, X85110

Test Results
Description (…) Meets specification
Moisture (NMT 0.5%) State range of values or highest value, trend

0.1-0.48%, slight increasing trend. For batch X05172, 0.48% at 6 Month.
Impurities State range of values or highest value, trend (for quantitative methods)
(Semi-quantitaive TLC-- complies )
Imp A: NMT 0.5% Imp A: 0.08 % to 0.32%, increasing trend

Imp B: NMT 0.3% Imp B: Up to 0.23%, no trend
Any unkown indi: NMT 0.2% Any unknown indi: up to 0.11% , no trend
Total imps: NMT 1.5% Total imps: 0.34%- 0.82%, increasing trend
Assay (90.0%-110.0%) State range of values or lowest value, trend
97.8-100.2%, no trend
Dissolution (NLT 75% (Q) in 30 mins) Individual values 81-92%, Average 85-89%, no trend
etc…
Note: When summarizing, the limits should be included in the stability summary
30 |
 When summarizing, the limits should be included in the stability summary
 Specifications get revised, sometimes by request. When asking for a

tighter limit, the biobatch results and the stability data need to be
referenced, and this must include accelerated data results
 Always request updated data while assessment is ongoing.
 When updated stability is reviewed, it is important to ensure it meets the

revised/current limits.
31 |
Summarizing impurities/degradants
 Impurities (TLC): Results are semi-quantitative, e.g. impurity A < 0.5%,

total < 1.0%
 Impurities (HPLC): Results must be quantitatively summarized for all

specified impurities. This tells:
 whether there are trends,
 which impurities are degradants
 Focus on the first digit after the decimal point, i.e. 0.X%, variability on the
second digit after decimal point is not critical, e.g. 0.02% Vs 0.07% may
not indicate an increasing trend due to the variability of method.
32 |
Summarizing dissolution data
 Dissolution limits should be expressed as a Q value (amount of API

expressed as % label content), in line with the harmonized chapters (USP,
BP, JP, PhInt)
 Q value means three stage testing:

 Stage 1 (6 units): each unit ≥ Q+5%
 Stage 2 (6 units): average of 12 units (S1 + S2) ≥ Q, no unit < Q-15%
 Stage 3 (12 units): average of 24 units (S1 + S2 +S3) ≥ Q, not more
than 2 units < Q-15%, no unit < Q-25%
Stage 1 is always tested. Stage 2 is tested only if stage 1 fails. Stage 3 is
tested only if stage 2 fails.
33 |
Example:
Test Results
Dissolution (NLT 75% (Q) in 30 mins) Results 82-94%, no trend
S1: each unit ≥ Q+5% (80%) Are the summarized values individual or average
values?
S2: Ave ≥ Q (75%) , no unit < Q-15% (60%) Does this meet the stage 1 limits?
S3: Ave ≥ Q (75%) , NMT 2 units < Q-15% (60%) ,
no unit < Q-25% (50%)
34 |
 Dissolution data - two critical factors to summarize:

 the individual values (to observe if it meets the limits)
 the average values (to observe a trend)
 The applicant must provide either individual results + average results

for each station (e.g. 94, 82, 90, 89, 90, 93, ave. 88)
 or, the range of individual results + average results for each station
(e.g. individual 82-94, ave. 88)
35 |
Example:
Test Results
Dissolution (NLT 75% (Q) in 30 mins) Results 82-94%, no trend
S1: each unit ≥ Q+5% (80%)

S2: Ave ≥ Q (75%) , no unit < Q-15% (60%)
Individual results 80-96%, Ave 82-94%, no trend. √
S3: Ave ≥ Q (75%) , NMT 2 units < Q-15% (60%) OR in example where S1 fails:
, no unit < Q-25% (50%) Individual results 78-99%, Ave 82-94%, stage 2
tested and met limits, slight decreasing trend. √
36 |
Overview

 Extrapolation
 Examples
37 |
Trends, Significant changes, OoS
 Variation: means you won’t usually have a perfect linear trend (analytical
variability, sample uniformity)
 Trends: if the majority of stations show a trend (downward, upward),
consider it a trend.
 OOT: analytical value outside our experience but within the specification (no
OOS)
 OOS: analytical value outside of the registered specification
38 |
“Significant Change”
 For an API: "significant change" is failure to meet the specification for any
parameter
 For an FPP, significant change is any of:

 Any degradation product exceeding its limit
 Failure in tests of appearance, physical attributes and functionality test,
e.g. colour, hardness, pH
 > 5% change in assay from initial, i.e. t0;
 failure to pass dissolution testing for 12 dosage units (fail S2)
39 |
Extrapolation
Extrapolation: Extend the retest period or shelf life beyond the period
covered by available long-term stability data
 A retest period or shelf life granted on the basis of extrapolation should

always be verified by additional long-term stability data as soon as these
data become available (commitments)
 For long term condition at zone IV (WHO PQTm), extrapolation should

be done cautiously. ICH Q1 guidance is for zone II, where there is
intermediate data to consider and provide additional assurance.
40 |
Extrapolation
ICH Q1E –extrapolation without statistical analysis
 No significant change at accelerated condition (6 months )

 Little/no change and little/no variability for accelerated and long term data
intended for storage at intended for storage at

25ºC or 30ºC refrigerator 2-8 ºC
Y= 2X Y= 1.5X
but NMT X + 12 months but NMT X + 6 months
X= Period covered by long-term data

Y= proposed retest period or shelf life
41 |
Extrapolation
ICH Q1E –extrapolation without statistical analysis
 No significant change at accelerated condition (6 months )

 change and/or variability for accelerated and/or long term data
intended for storage at intended for storage at

25ºC or 30ºC refrigerator 2-8 ºC
Y= 1.5X NMT X + 3 months
but NMT X + 6 months
X= Period covered by long-term data

Y= proposed retest period or shelf life
42 |
Extrapolation
 For products for zone IVB, extrapolation should be done cautiously. ICH
Q1 guidance is for zone II (25C/60%), where there is intermediate data to
consider and provide additional assurance.
 For zone IVa/IVb, if accelerated shows significant change, there is no

intermediate condition.
 Statistic analysis may not available/meaningful when there are limited

number of test batches
43 |
In case significant changes are observed
Stability is complex and must be considered case-by-case, but various
considerations can be weighed to help make a decision, including:
 extent of change
 “Significant changes” that are not failures, e.g. Assay decrease from
100% to 94.0%;
 Marginal failures, e.g. 89.6% assay for 90.0-110.0% limit;
 Catastrophic failures, e.g. 70% assay, 20% degradation
 time of change, e.g. “Significant changes” observed at 1 months can be

considered differently than at 6 months
 packaging involved
44 |
In case significant changes are observed
Possible responses:
 No allowed extrapolation
 Shorter shelf-life than covered by long term data.
 If long term data is at 30ºC/75%, labeling may be “below 25ºC, avoid

excursions above 30ºC
 Improve the packaging. If multiple proposed containers and the problem is

not observed in all containers, they can withdraw the problem container(s).
 A serious problem may require reformulation of the FPP (e.g. known

hygroscopic API and wet granulation).
45 |
 Begin with the accelerated condition, and the intermediate condition if

appropriate, then review the long term data
 Tabulate and/or plot stability data on all attributes at all storage conditions
and evaluate each attribute separately
 Identify any trends, significant changes, out of specification results (OoS)
 Information of innovator (e.g. packaging of innovator), literature,

prequalified products may help in the review
 Refer to ICH Q1E appendix A decision Tree for Retest period or shelf life
Estimation
46 |
Example #1
Problem: Data are provided over the retest period

at long-term conditions. Data at accelerated conditions are
not available. The applicant states that
accelerated data are not necessary because long-term data
cover the whole proposed retest period. Is it acceptable?
47 |
Example #1
Problem: Data are provided over the retest period

at long-term conditions. Data at accelerated conditions are
not available. The applicant states that
accelerated data are not necessary because long-term data
cover the whole proposed retest period. Is it acceptable?
Approach: Accelerated data are not only to support extrapolation, they are
also to cover excursions outside the long-term storage conditions.
Accelerated data are always required to support a retest or shelf-life
period.
48 |
Example #2
 Data are provided for 12 months at 30◦C/75% and 6 months at 40◦C/75%.

No significant change is noted. No/little change and variability. How long
could shelf life be granted?
49 |
Example #2

No significant change is noted. No/little change and variability. How long
could shelf life be granted?
 Answer:
 A provisional shelf-life of 24 months (12 months + 12 months) can be
assigned.
 Storage statement “Do not store above 30◦C”.
 Commitment to continue the statility study should be provided
50 |
Example #3

 Significant change is noted at 40◦C/75% at 6 months time point.
 Data at 30◦C/75% are in compliance with the specification without
significant trends.
 There is no intermediate storage condition.
How long could shelf life be granted?
51 |
Example #3

 Significant change is noted at 40◦C/75% at 6 months time point.
 Data at 30◦C/75% are in compliance with the specification without
significant trends.
 There is no intermediate storage condition.
How long could shelf life be granted?
Answer:
 A shelf-life of 18 months can be assigned. The shelf-life is
based on real time data due to significant change observed
at accelerated conditions.
 Storage statement “Do not store above 30◦C”.
 Commitment to charge additional batches to stability studies
52 |
53 |

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Stability testing

 Understand the molecule

 Establish a retest period (API) or shelf-life & storage conditions

 Establish shelf life acceptance criteria of Specification

 Validate analytical methods

 Stress testing (photostability)

Stability testing under conditions exceeding those used for accelerated

 establish the inherent stability characteristics of the molecule

 establish the degradation pathways

 identify the likely degradation products

 validate the stability indication power of the analytical methods

 formulation development, manufacturing process development

 When available, it is acceptable to provide relevant data published in the

 No detailed stress testing strategy in Guidelines, except for

experimental conditions and duration may need to be varied depending

 Generic guideline refers to FDC guideline appendix 3, table A.1 (TRS

 How much stressing is enough ?

 balance between "purposeful degradation" and irrelevant artifacts (e.g.,

 degradation products not formed during accelerated or long-term stability

 Check compendial statement, e.g “protect from light”.

 Check if conditions are adequate

 Check the extent of degradation

 Conclude on the degradation pathways, stability nature of the API

 spend excessive time with degradants generated in stress studies if they

 The impurities/degradants that must be closely investigated are those

 Photostability Studies should be conducted on at least one primary batch;

If any stage is photostable, no need to continue, e.g.:

if API shown photostable, then FPP testing is not necessary

 Either photostability should be demonstrated or light protection of packaging

 A light sensitive product should be provided in light protective packaging. Be

 Stress testing (photostability)

 Number of batch(es) and batch sizes

 Container closure system (s)

 Tests and acceptance criteria (reference to test methods)

 A) a retest period for an API: 3 API batches, at least pilot scale

 Should be the container proposed for storage/distribution including any

Generally only a consideration for liquids and semi-solids.

Accelerated : Minimum three points including t0 and tfinal, eg 0, 3, 6.

Storage temperature Relative humidity (%) Minimum time period

Accelerated 40±2 75±5 6

Long-term 30±2 65±5 (API only) or 6

* Where long-term conditions are 30ºC±2ºC/65%±5%RH or 30ºC±2ºC/75%±5%RH, there

Monitor parameters susceptible to change:

 Physical: description, moisture;

 Chemical: assay, degradants;

 Performance tests: e.g. dissolution, disintegration (e.g. dispersible tablets)

 Efficacy of additives: Preservative content;

Unlikely to change during storage:

 Stability data in tables or graphs or both

 Stress testing (photostability)

 Quality Overall Summary - Product Dossier (QOS-PD) 2.3.S.7 & 2.3.P.8

 Use the mock dossier for example

 Quality Overall Summary - Product Dossier (QOS-PD) 2.3.S.7 & 2.3.P.8

40°C±2°C/75%±5%RH X95910 100,000 tablets Completed – Initial, 1M, 2M,

Example: 40°C±2°C/75%±5%RH, 6 Months. X95910, X05172, X85110

Description (…) Meets specification

Moisture (NMT 0.5%) State range of values or highest value, trend

Imp A: NMT 0.5% Imp A: 0.08 % to 0.32%, increasing trend

 When summarizing, the limits should be included in the stability summary

 Specifications get revised, sometimes by request. When asking for a

 Always request updated data while assessment is ongoing.

 When updated stability is reviewed, it is important to ensure it meets the

 Impurities (TLC): Results are semi-quantitative, e.g. impurity A < 0.5%,