1. Registration requirements for vaccines -Strategies to implement VICH GLs-
Takashi KOZASA, DVM
National Veterinary Assay Laboratory, Ministry of Agriculture, Forestry and Fisheries, Tokyo, Japan
Presented at 8th VICH Outreach Aires, March 1, 2017

2. [Chapter 1.1.8.] Principles of veterinary vaccine production
Vaccines
-OIE Terrestrial Manual (2015)-
[Chapter ] Principles of veterinary vaccine production
A reliable supply of pure, safe, potent, and effective vaccines is essential for maintenance of animal health and the successful operation of animal health programmes. Immunisation of animals with high quality vaccines is the primary means of control for many animal diseases. In other cases, vaccines are used in conjunction with national disease control or eradication programmes.

3. 2017/10/5
VICH guidelines and dossier requirements for veterinary vaccines in Japan

4. 2017/10/5
The Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics
Article 14*1
A person intending to market a drug*2 , a quasi-drug*3, a cosmetic containing the ingredients designated by the Minister or a medical device*4 shall, for each product, obtain marketing approval of the Minister with respect to its marketing.
*1 This English text of law is the previous text before revision.
*2 Excluding drugs with the standards specified and designated by the Minister and in vitro diagnostic reagents specified under Article 23-2, Paragraph 1
*3 Excluding those with the standards established by the Minister
*4 Excluding general medical devices and controlled medical devices designated by the Minister pursuant to the provisions of the same paragraph

5. Application for Marketing Approval
Composition of dossiers (application form with background study data)
2017/10/5
Application for Marketing Approval
Name and address of manufacturer
License No. of manufacturer
Type of license
Name of drug
Ingredients and quantities
Manufacturing method
Administration and dosage
Label claim
Condition for storage
Shelf life
Quality control testing and acceptance criterion
References
App.1: Origin and background of the discovery
App.2: Physicochemical properties
App.3: Production protocol
App.5: Stability
App.9: Target Animal Safety
App.10: Efficacy
App.14: Clinical trial

6. Appendix 1 The origin and background of the development
2017/10/5
Appendix 1 The origin and background of the development
Purpose of development
Information on the target disease(s)
Information on outbreaks of the target disease(s) in Japan
Information on the similar products approved in foreign countries
Component comparison with similar vaccines already approved in Japan

7. Appendix 2 Physicochemical property of vaccine strain
2017/10/5
Appendix 2 Physicochemical property of vaccine strain
Origin of the strain and seed production process
Attenuation, strain marker and stability (live vaccine)
Excretion and cohabitation infection (live vaccine)
Immunogenicity
Absence of reversion to virulent form (VICH GL41)
Safety of master seed in target animal
Quality control testing (seeds, in-process and batch release) and acceptance criterion

8. Absence of reversion to virulent form (VICH GL41)
(ex. Poultry viral vaccine)
5th passage
Material
104TCID50 /ml, 1 ml, per oral
MS virus
104TCID50 /ml, 1 ml, per oral
Observe clinical signs for 21 days and compare between the two groups
Virus in 5th passage is
more virulent than MS
Same result
No reversion to virulence
Reversion to virulence

9. Quality control testing (batch release)
Testing for:
Acceptance criterion (example)
Moisture (VICH GL26)
<3%
Residual formaldehyde (VICH GL25)
<0.05vol%
Sterility
No bacteria or fungi should be present.
Mycoplasma (VICH GL34)
No mycoplasma should be present.
Virus content
At least 104TCID50 /dose
Target animal batch safety (Waiver of TABST: VICH GL50R* and 55*)
No adverse effects should be observed.
Potency
Neutralizing antibody titers >8 in vaccinated animals
*GL50 is available.
Revision of GL50 and development of GL55: in-process

10. Appendix 3 Protocol of production
2017/10/5
Appendix 3 Protocol of production
Live-attenuated viral vaccine
Inoculate production seed virus in eggs
Incubate for XXX days at 37 ˚C
2 Harvest, filter and centrifuge virus fluid
3 Dilute and add stabilizer
4 Place aliquots in vials and freeze-dry

11. Appendix 5 Stability of Final product (Shelf life)
2017/10/5
Appendix 5 Stability of Final product (Shelf life)
Method: Long-term stability test
Sample: Final products
Number of sample: 3 batches
Test interval : every 3 (6, 12) months
Test items: All items of the final products

12. Appendix 9 Target animal Safety test (TAS)
2017/10/5
Appendix 9 Target animal Safety test (TAS)
GLP study
Method: VICH GL44
Material: final products
Number of Animals: 8 animals in each group
Administration dose:
Live vaccine given at 10 doses / animal
Inactivated vaccine given at 1 dose / animal
Data Collection:
General clinical observations (vitality, diarrhea, respiration, body weight)
Injection site (histopathologically after euthanasia)

13. Minimum effective dose Minimum effective antibody titer
2017/10/5
Appendix 10 Efficacy
Minimum effective dose
Minimum effective antibody titer
Comparative study on sensitivity by age, breed and administration route
Influence of maternal antibody on vaccination

14. Appendix 14 Clinical trial
2017/10/5
Appendix 14 Clinical trial
GCP study (VICH GL9)
Objective :
To evaluate the efficacy and safety of the vaccine in the field
Samples: Final products
Number of test sites: More than 2 sites
Number of Animals:
≥ 200 chickens
≥ 60 head for mammals
Test period:
Adequate period for evaluation of safety and efficacy of the vaccine in field

15. VICH guidelines for veterinary vaccines
At least 6 guidelines have been developed exclusively for vaccines.
GCP and pharmacovigilance guidelines cover vaccines.
Additional guidelines (e.g. quality) can be applied for veterinary vaccines.
GL50R (Waiver of TABST for inactivated vaccines) and GL55 (Waiver of TABST for live vaccines) are in the final stage of development.
VICH BQM EWG is currently working on topics on the waiver of LABST and extraneous virus testing.
VOF members do not have to implement all the guidelines at once.
What kind of guidelines is needed in your country?