Transcript Stability study of DS and DP

Stability study of DS and DP
Patchara Kootiratrakarn
30 April 2016
Table of content
 CTD format for DS stability study (3.2.S.7)
 CTD format for DP stability study (3.2.P.8)
 3.2.P.8.1 stability summary and conclusion
 3.2.P.8.2 post approval stability protocol and stability commitment
 3.2.P.8.3 stability data
 Type of stability study
 Standard stability study (real time, accelerated etc)
 Additional stability study (photo, stress, ECTC etc)
 Stability study of diluent
 Recommendations
CTD format for DS and DP stability study
 CTD section 3.2.S.7 & CTD 3.2.P.8
 Stability summary and conclusion
 Post-approval stability protocol and stability commitment
 Stability data
CTD format for DS and DP stability study
 3.2.S.7.1 & 3.2.P.8.1 Stability summary and conclusion
 Introduction and overview of stability study
 Stability protocol

Batch tested

Summary of stability protocol
 Result

Real time real condition (long term)

Accelerated condition

Post reconstitution condition
 conclusion
CTD format for DS and DP stability study
 3.2.S.7.1 & 3.2.P.8.1 Stability summary and conclusion
 Introduction and overview of stability study
Conditions of study
Drug Product
Validation
batches
Conditions
Presentation
Total duration
Status of study
Recommended storage Freeze-dried cake of
temperature +5°C ± 3°C 0.5 mL filled in 3 mL
Accelerated conditions: borosilicate glass vial
Type I
+25°C ± 2°C
36 months
Ongoing
9 months
Ongoing
Accelerated conditions:
+37°C ± 2°C
21 days
Completed
Post reconstitution
conditions: +5°C ± 3°C
6 hours
Completed
Post reconstitution
conditions:
+25°C ± 2°C
6 hours
Completed
CTD format for DS and DP stability study
 3.2.S.7.1 & 3.2.P.8.1 Stability summary and conclusion
 Introduction and overview of stability study
 Stability protocol

Batch tested
Batch number
Date of
manufacture
Use of the
batches
Manufacturing
site
CTD format for DS and DP stability study
 3.2.S.7.1 & 3.2.P.8.1 Stability summary and conclusion
 Introduction and overview of stability study
 Stability protocol

Batch tested

Summary of stability protocol
Test parameter
Appearance
Method
Acceptance
criteria
Ph. Eur. 2.9.20
- Before reconstitution
- Yellow to pinkish
homogeneous cake
- After reconstitution
- Amber to pink
suspension
Study condition
Frequency of
testing
Long term conditions:
+5°C ± 3°C
T0, 3, 6, 9, 12, 18, 24, 30
and 36 months
Accelerated conditions:
+25°C ± 2°C
T0, 1, 3, 6, and 9 months
Accelerated conditions:
+37°C ± 2°C
T0, 7, 14, and 21 days
CTD format for DS and DP stability study
 3.2.S.7.2 & 3.2.P.8.2 Post-approval stability protocol and stability
commitment
The applicant commits to completing the on-going stability studies as outlined
in 3.2.P.8.1 Stability Summary and Conclusions on the 3 validation batches of
Drug Product. Stability data will be provided when the 3–year data is
available.
The applicant also commits to provide a photostability study on one batch, as
well as ECTC of 3 commercial batches of DP. Stability data will be provided
when available.
CTD format for DS and DP stability study
 3.2.S.7.3 & 3.2.P.8.3 Stability data
 Analytical test methods and procedures
 Results

Batch information overview

Results of stability tests under long term conditions

Results of stability tests under accelerated conditions

Results of stability tests after reconstitution
CTD format for DS and DP stability study
 3.2.S.7.3 & 3.2.P.8.3 Stability data
 Analytical test methods and procedures
Test
Method
Appearance (before and after reconstitution)
Ph. Eur. 2.9.20
Reconstitution time
In house described in 3.2.P.5.2 Analytical
Procedures
pH
Ph. Eur. 2.2.3
CTD format for DS and DP stability study
 3.2.S.7.3 & 3.2.P.8.3 Stability data
 Analytical test methods and procedures
 Results

DP batch
number
Batch information overview
Date of
manufacture of
the DP
Batch size
Corresponding
Date of
Corresponding
Date of
FBP batch
manufacture of
DS
manufacture of
number
the FBP
the DS
CTD format for DS and DP stability study
 3.2.S.7.3 & 3.2.P.8.3 Stability data
 Analytical test methods and procedures
 Results
Tests

Batch information overview

Results of stability tests under long term conditions
Acceptance criteria
- Appearance
before
reconstitution
- Yellow to pinkish
homogeneous cake
- Appearance
after
reconstitution
- Amber to pink
suspension
T0
3m
6m
9m
12m
18m
24m
30m
36m
yellow
homogeneous
retracted cake
yellow
homogeneous
retracted cake
TBD
TBD
TBD
TBD
TBD
TBD
TBD
Light amber
suspension
Light amber
suspension
TBD
TBD
TBD
TBD
TBD
TBD
TBD
CTD format for DS and DP stability study
 3.2.S.7.3 & 3.2.P.8.3 Stability data
 Analytical test methods and procedures
 Results

Batch information overview

Results of stability tests under long term conditions

Results of stability tests under accelerated conditions
Tests
T0
- Appearance before
reconstitution
- Yellow to pinkish
homogeneous cake
- Appearance after
reconstitution
- Amber to pink
suspension
Tests
- Appearance before
reconstitution
- Appearance after
reconstitution
1m
3m
6m
9m
yellow homogeneous
retracted cake
TBD
TBD
TBD
Light amber
suspension
TBD
TBD
TBD
T0
- Yellow to pinkish
homogeneous cake
- Amber to pink
suspension
7 days
14 days
21 days
Yellow collapsed cake
Yellow collapsed cake
Yellow collapsed cake
Light amber suspension
Light amber suspension
Light amber suspension
CTD format for DS and DP stability study
 3.2.S.7.3 & 3.2.P.8.3 Stability data
 Analytical test methods and procedures
 Results

Batch information overview

Results of stability tests under long term conditions

Results of stability tests under accelerated conditions

Results of stability tests after reconstitution
Tests
- Appearance before
reconstitution
- Appearance after
reconstitution
Acceptance criteria
- Yellow to pinkish
homogeneous cake
- Amber to pink
suspension
T0
1 hour
2 hours
6 hours
yellow homogeneous
retracted cake
TBD
TBD
TBD
Light amber
suspension
TBD
TBD
TBD
Vaccine stability study
 Why does stability study of product have to be performed?
To determined product shelf life.
To prove the ability of a vaccine retaining its chemical, physical,
microbiological and biological properties within specified limits throughout its
shelf-life.
Type of Stability study of vaccine
การศึกษาความคงตัวของวัคซีน มีหลายประเภท ได้แก่
การศึกษาความคงตัวตามระยะเวลาจริงทีเ่ ก็บ ณ อุณหภูมทิ ก่ี าหนด คือที่ 2-8°C
การศึกษาความคงตัวแบบเร่ง ทีเ่ ก็บ ณ อุณหภูมิ 25±2°C และ 37±2°C
การศึกษาความคงตัวของวัคซีนหลังการละลาย และนาไปเก็บทีอ่ ณ
ุ หภูมิ 2-8°C และ 25±2°C
การศึกษาความคงตัวโดยการสัมผัสแสง photo-stability
Stress stability study
Extended Controlled Temperature Conditions (ECTC)
On-going stability study
Photo-stability study
 Study design
 Normally, photostability testing is carried out on a single batch of material selected.
Under some circumstances these studies should be repeated if certain variations and
changes are made to the product (e.g., formulation, packaging).
 A systematic approach to photostability testing is recommended covering, as
appropriate, studies such as

i) Tests on the drug substance;
 ii) Tests on the exposed drug product outside of the immediate pack; and if necessary;
 iii) Tests on the drug product in the immediate pack; and if necessary;
 iv) Tests on the drug product in the marketing pack.
 samples should be exposed to light providing an overall illumination of not less than 1.2
million lux hours and an integrated near ultraviolet energy of not less than 200 watt
hours/square meter.
 If protected samples (e.g., wrapped in aluminum foil) are used as dark controls to
evaluate the contribution of thermally induced change to the total observed change,
these should be placed alongside the authentic sample.
Stress stability study condition
 Stress stability study is voluntary by the manufacturer
 Study design
 One batch of commercial manufacturing batch performed comparing with ongoing stability study
 Testing time point is assigned following on-going stability study
 Additional condition: storage in controlled temperature chain (CTC) condition then
relocate to expose at higher temperature for a period after returning to continue in
CTC storage condition up to its shelf life.
10 m at 2-8˚C
2m at
25±2˚C
24 m at 2-8˚C up to product shelf life
On going stability study storage at 2-8˚C
Extended Controlled Temperature
Conditions (ECTC)
 New proposal from WHO/ECTC_DRAFT/21 MAY 2015
 Approved short term temperature conditions above those defined for long
term storage, transportation and use for a given product, immediately prior
to administration.
 Current WHO program conditions for Controlled Temperature Chain (CTC)
include a single exposure just prior to administration, tolerating ambient
temperatures of at least 40°C for a limited duration of at least three days,
with the CTC provision included in the licensure by the relevant RNA and
the WHO pre-qualification.
 When the accelerated temperature conditions are equivalent to or higher
than the ECTC condition under evaluation, the accelerated stability data
can be considered for support of allowed exposure conditions.
On-going stability study
 1 commercial batch of each manufacturing year has to be put in an ongoing stability study
 Study design:
 Product is kept at CTC condition defining in the licensing document
 Testing time point is assigned with at least 4 testing points up to product shelf life
e.g. T0, T12, T24, and T36
 Any batch experienced with deviation condition can be put in this study
 if there is/are any process validation batch(es) due to any constrain, e.g. change
in manufacturing process, an going stability study of the year can be skipped if
real time condition of the batch is performed.
Stability study of diluent
 Diluent Stability study profile should be demonstrated according to its
storage condition and shelf life with real time and real condition stability
study.
 Stability study of diluent should be independently performed from vaccine
in the same manner and condition with vaccine.
 Diluent used in reconstituting vaccine should be identified with the lot
number and expiry date.
 In case shelf life of diluent is shorter than vaccine, when package, the
expiry on the package should be labeled with the shorter one.
Recommendations
 There should be an identifiable label to every single vial of sample.
 There should be 30% excess of sample for stability study and storage in upside down
position in order to detect any absorbable or reachable from rubber stopper along
product shelf life.
 Some specific test can be performed only at T0 and Tend e.g. sterility test, endotoxin
test and abnormal toxicity test.
 Some specific test can be performed only at T0 e.g. identity test.
 For in-used stability study of single dose presentation, 3 time points of test is
recommended e.g. 0, 1, 2 hours after reconstitution
 For post reconstitution of multi-dose presentation, 4 time points is recommended e.g. 0,
3, 6, 9 hours after reconstitution.
 Trend analysis of each quantitative test has to be performed and followed up all along
the stability study.
 Any change or deviation occurred during stability study, should be recorded in the
final stability report.