1. Stability study of DS and DP Patchara Kootiratrakarn 30 April 2016

2. 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

3. 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

4. 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

5. 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 Drug Product Conditions of study Status of study ConditionsPresentationTotal duration Validation batches Recommended storage temperature +5°C ± 3°C Freeze ‑ dried cake of 0.5 mL filled in 3 mL borosilicate glass vial Type I 36 monthsOngoing Accelerated conditions: +25°C ± 2°C 9 monthsOngoing Accelerated conditions: +37°C ± 2°C 21 daysCompleted Post reconstitution conditions: +5°C ± 3°C 6 hoursCompleted Post reconstitution conditions: +25°C ± 2°C 6 hoursCompleted

6. 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 numberDate of manufacture Use of the batches Manufacturing site

7. 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 parameterMethodAcceptance criteria Study conditionFrequency of testing AppearancePh. Eur. 2.9.20 Long term conditions: +5°C ± 3°C T0, 3, 6, 9, 12, 18, 24, 30 and 36 months - Before reconstitution- Yellow to pinkish homogeneous cake - After reconstitution- Amber to pink suspension 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

8. 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.3.2.P.8.1 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.

9. 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

10. 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 TestMethod Appearance (before and after reconstitution)Ph. Eur. 2.9.20 Reconstitution time In house described in 3.2.P.5.2 Analytical Procedures3.2.P.5.2 pH Ph. Eur. 2.2.3

11. 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 DP batch number Date of manufacture of the DP Batch sizeCorresponding FBP batch number Date of manufacture of the FBP Corresponding DS Date of manufacture of the DS

12. 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 TestsAcceptance criteriaT03m6m9m12m18m24m30m36m - Appearance before reconstitution - Yellow to pinkish homogeneous cake yellow homogeneous retracted cake TBD - Appearance after reconstitution - Amber to pink suspension Light amber suspension TBD

13. 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 TestsT01m3m6m9m - Appearance before reconstitution - Yellow to pinkish homogeneous cake yellow homogeneous retracted cake TBD - Appearance after reconstitution - Amber to pink suspension Light amber suspension TBD TestsT07 days14 days21 days - Appearance before reconstitution - Yellow to pinkish homogeneous cake Yellow collapsed cake - Appearance after reconstitution - Amber to pink suspension Light amber suspension

14. 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 TestsAcceptance criteriaT01 hour2 hours6 hours - Appearance before reconstitution - Yellow to pinkish homogeneous cake yellow homogeneous retracted cake TBD - Appearance after reconstitution - Amber to pink suspension Light amber suspension TBD

15. 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.

16. Type of Stability study of vaccine  การศึกษาความคงตัวของวัคซีน มีหลายประเภท ได้แก่  การศึกษาความคงตัวตามระยะเวลาจริงที่เก็บ ณ อุณหภูมิที่ กำหนด คือที่ 2-8°C  การศึกษาความคงตัวแบบเร่ง ที่เก็บ ณ อุณหภูมิ 25±2°C และ 37±2°C  การศึกษาความคงตัวของวัคซีนหลังการละลาย และนำไปเก็บที่ อุณหภูมิ 2-8°C และ 25±2°C  การศึกษาความคงตัวโดยการสัมผัสแสง photo-stability  Stress stability study  Extended Controlled Temperature Conditions (ECTC)  On-going stability study

17. 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.

18. Stress stability study condition  Stress stability study is voluntary by the manufacturer  Study design  One batch of commercial manufacturing batch performed comparing with on- going 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

19. 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.

20. On-going stability study  1 commercial batch of each manufacturing year has to be put in an on- going 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.

21. 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.

22. 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.