1. Review of the VICH guidelines on Biologicals
Good afternoon. My name is Kota Sato, a chairperson of the expert working group for biologicals quality monitoring since this May.
Today, I would like to talk about quality control measures for vaccine in Japan and discuss the VICH guidelines that is related to vaccine.
Kota SATO, DVM PhD
National Veterinary Assay Laboratory, Ministry of Agriculture, Forestry and Fisheries, Tokyo, Japan
9th VICH Outreach Forum, November, 2017

2. VICH guidelines for veterinary vaccines
Introduction : Quality Control of Veterinary Biologicals (vaccine) in Japan
VICH guidelines for veterinary vaccines
My presentation is divided into two parts as shown here. Firstly, I will give you a brief introduction on the quality control in Japan. And, next part, I will talk about the VICH guidelines related to biologicals, including vaccine.

3. VICH guidelines for veterinary vaccines
Introduction : Quality Control of Veterinary Biologicals (vaccine) in Japan
VICH guidelines for veterinary vaccines
I would like to start by talking about Japanese measures and systems.

4. Quality in Vaccination Practice
Subjects to ensure quality of product/practice
Quality in Vaccination Practice
We keep quality of animal drugs, including biologicals and vaccine , by these 4steps as shown in this cartoon as 4 pillars.
Actually, these steps are products, distribution, usage and monitoring aftrer selling.
These 4 pillars support the quality of vaccine products and veterinary practice.
Each of the pillar plays an important role for quality control.
Products Distribution Usage Monitoring
Four pillars of subject required to ensure the quality of
Vaccine products and relating veterinary practice

5. Vaccine Quality Control Overview
Subject
Purpose
Measure/System
Products
Quality/Safety/Efficacy
License for Manufacturing
License for Marketing Authorization Holder (MAH)
Pre/Post-marketing evaluation
Seed-lot system / GMP
National Assay
Distribution
Proper storage/transport
(cold chain)
Proper retailing
Sales by vet. oversight
License for Retailing
Prescription
Usage
Vet. consultation
Responsive Use
Code of practice
Monitoring
Adverse effect
Vaccine break
Pharmacovigilance
This slide shows the overview of the vaccine quality control.
Most left column is Subjects as shown in previous slide. In order to achieve the purposes for each step, we apply these measures and systems.
For example, to keep the quality, safety and efficacy of the vaccine, we have these strategies, such as Licenses for manufacturing, and market authorization holder, namely selling the drugs. Evaluations before and after selling the drug, and seed-lot system combined with GMP. Finally, we are also doing national assay for final batch product of vaccine.
Distribution of vaccine is also regulated by these system, in order to keep proper strage and trasnport, or retailing.
Usage by veterinarian is also another point for quality control because the apropriate veterinary practice is guarateed by these code and measures.
Finally, Monitoring is also quite important to prevent from the side effects or ineffective vaccine, that is inadequately produce or used after selling investigation. That step is refered to as pharmacovigilance.

6. Products License for Manufacturing
Anyone who manufacture VMPs in business has to obtain the manufacturing license (renewal: 5 years).
The license guarantees quality of facilities in which a VMP is manufactured, tested or stored.
License for Marketing Authorization Holder (MAH)
A person intended to market release of VMPs shall obtain the license for MAH
(renewal: 5 years).
Applicant shall comply with the standards of quality control of VMPs and the standards for post-marketing safety management.
Next, let’s look at the detail for each step.
Firstly, I discuss about measures for product level.
License for manufacturing; we restrict the production of animal drugs to person or company that appropriately make good products.
(Read)
Next, the license for marketing authorization holder, abbreviated as MAH. License for MAH is necessary for market release of drugs.
Legally,

7. Products Pre-marketing evaluation
A person intended to market a biological product for veterinary use shall obtain marketing approval of Minister of Agriculture, Forestry and Fisheries
Technical dossier Components
Origin and background
Physicochemical and biological properties
Production protocol
Stability
Target Animal Safety
Efficacy
Clinical trial
Another system for quality control is evaluation.
Pre-marketing evaluation is a very difficult step for pharmaceutical company even if it is for animal use.
Each company that intend to market drugs, they must obtain approval from the ministry of agriculture.
They must prepare a large numbers of paper, that is “Technical dossier components” to pass the evaluation.
That contains (Read)
Post-marketing evaluation is also an important step for quality control, (Read)
Post-marketing evaluation
Efficacy and safety of a new VMPs are reviewed on the basis of field investigations that conducted by MAH within 6 years after the approval of a VMP.

8. Products Seed-lot system with GMP Definitive specification
Full testing data
Extraneous virus
Target animal safety
Pathogenicity reversion
Sterility, Mycoplasma …etc.
Master Seed [PassX]
Passages
Working Seed
[PassX+3]
Minimum specification with limited testing, e.g., Sterility, Mycoplasma…
Passages
Limited passage number from
Master Seed to Final Product,
e.g., Pass X+5
Production Seed
[PassX+4]
Next, I would like to stress that Seed-lot system combined with GMP is also very important step for quality control, and these combination can be a prerequisite for actual implementation of VICH guidelines for vaccine.
The principle of quality control by this system is guaranteed by thorough examination of master seed from which the final vaccine product originates. In addition, decrease the passage number as possible and examine the flow of production system, including materials and methods, such as human and machines, culture media, animal sera by GMP measure. Namely, we aim to keep the quality by checking up-steram original source and how to make, not by assessing the final products. By doing so, we can make vaccine of constant quality and avoid labor consuming final product assay.
National assay for final products is currently performed for every vaccine in Japan, but recently many vaccine are made by seed-lot system. And we regulators intend to exempt the national assay for the products that are made under this system.
Therefore, we see severely the master seed and production process currently.
National Assay
Final product shall be assayed by JMAFF before market release.
National assay can be exempted when the production process conform to the seed-lot system and GMP standards .
Bulk
Final Product
[Pass X+5]

9. Distribution License for Retailing
Anyone shall not retail VMPs without a license for VMP retailer.
A prefectural governor grants the license (renewal:6 years).
2,000 veterinary pharmaceutical inspectors are stationed throughout the nation to make on-site inspection;
To confirm compliance with the law and standards
To find unapproved, defective or illegally labeled VMPs.
To uncover false, exaggerated advertisement or non-licensed retailer.
Next component is regulation for distribution of vaccine. In order to sell animal drugs to others, they need License for retailing. The retailing of drugs is very severely restricted in Japan.
(Read)

10. Distribution / Usage Prescription system
The Minister designates certain VMPs which require prescriptions issued by a veterinarian.
Vaccines, antibiotics, hormones, etc.
Veterinarian shall not issue a prescription without his/her own medical examination.
Fine <$US 2,000, when violated.
Retailer shall not sell the designated VMPs to a customer who does not have a prescription.
<3years of prison and/or fine <$US 30,000, when violated.
Another most important system to keep proper distribution and usage of animal drugs is “prescription system”.
(Read)
This system is applied to important drugs such as vaccines, antibiotics, hormones and so on. Important drugs means that, such drugs can be dangerous to animals, or people who eat those animals, or environment in a veiw point of one-health.
Namely, only veterinarian can prescript such important drugs. So usage of such drugs must be restricted by veterinarian in his or her responsibility.
Thus, they must examine the patient. If they sell drugs without examination, they can pay fine as much as 2,000 dollars.
In addition, retailer is also restricted to sell such drugs.
Violation gives them 3 years prison and/or 30,000 dollars. Both of them is possible. I think it is very severe.
This situation demonstrates that prescription system is critically important in veterinary medicine of Japan.
The prescription system is not established in developing countries. I would like to stress that we need to cooperate internationaly to build up this fundamental system in the world.

11. Usage
Code of practice
Any veterinarian shall not provide vaccination to the animals without his/her own medical examination.
Responsive and proper use
Follow the direction on the label
A vaccine product should not be mixed with other VMPs when administered to the animals to avoid,
Unpredictable adverse effects
Delay in residue depletion of mixed VMP
Keep the preservation temperature until the time of administration
Exposure to hot weather dramatically reduce the quality of vaccine.

12. Monitoring Pharmacovigilance
When marketing authorization holders of VMPs are informed of any adverse reactions, they must report them to the Minister.
Veterinarians shall submit reports to the Minister when acknowledged the occurrence of ;
Any disability or death caused by adverse reactions of the product, or
Infectious disease that is hazardous to the animal and public health with respect to administration of vaccine.
(Sometimes help finding counterfeit drug)

13. VICH guidelines for veterinary vaccines
Introduction : Quality Control of Veterinary Biologicals (vaccine) in Japan
VICH guidelines for veterinary vaccines
Next theme is VICH guidelines for veterinary vaccines.

14. VICH guidelines for veterinary vaccines
Guidelines finalized by 2017
Moisture testing (VICH GL26)
Residual formaldehyde testing (VICH GL25)
Mycoplasma contamination testing (VICH GL34)
Target animal safety testing (VICH GL44)
Waiver of Target animal batch safety testing
(Inactivated vaccine: VICH GL50R)
(live vaccine: VICH GL55)
Currently, we have only 6 guidelines that is applied to exclusively to vaccines. This table shows the actually implemented guidelines for vaccine in VICH.
They are
(Read)
In addition to these, other general guidelines for animal drugs are also applied to vaccnin products.

15. Among these guidelines, I would like to introduce one exceptional guidelines for vaccine.
That is abbreviated as TABST
The formal name is “Read”

16. VICH 3Rs Statement
At its 19th meeting in 2007 in USA, the SC reiterated its ambition to minimise animal testing
Support for the 3Rs principle
replacement, refinement and reduction
[Statement of Principle for VICH - Alternatives to Animal Testing (VICH/07/038-Final; 18/09/2007)]
As you may know, 3R principle for experimental animals have been widely accepted in world-wide scientist. 3R refers to as Reduction, Replacement and Refinement of the procedure. This principle was also discussed in VICH meeting. At its 19th meeting in USA, SC decided to accept the principles and published the statement to achieve the goal.

17. What is batch safety test (BST) ?
Tests in target and/or laboratory animals
For Final product of broad group of vaccines
Considered as general safety tests
Vaccines may change its safety/toxicity batch to batch
Need assurance that a batch will be safe
BST should uncover;
Abnormal local or systemic reactions (EU)
Unfavorable reactions (US)
Abnormal changes (Japan)
Most batch safety tests in laboratory and/or target animals on final product can be considered as general safety tests. They apply to a broad group of vaccines and should provide some assurance that the product will be safe in the target species, i.e. it should reveal “abnormal local or systemic reactions” (European Pharmacopoeia) or “unfavorable reactions attributable to the biological product ...” (Title 9. United States Code of Federal Regulations) or “no abnormal changes” (Minimum Requirements for Veterinary Biological Products under the Pharmaceutical Affairs Law in Japan).

18. Are BSTs for vaccines necessary?
Decreased concern on adverse reactions of vaccines
Due to the Improvements in
-Quality of raw materials
-Culture / Purification method
-Assay method
-Seed lot system / GMP standard
-Safety testing under GLP standard
Moreover, decrease in concerns on adverse effect of vaccine also help to turn the direction to quit BST.
Such improvements include
(Read)
In other words, these are the prerequisites for developing guidelines to waive the BST.

19. What is TABST GL? Formal name: Very exceptional in whole VICH GLs
Harmonisation of criteria to waive target animal batch safety testing for inactivated vaccines for veterinary use
Very exceptional in whole VICH GLs
Usual GLs are test requirement for registration
TABST GL is applied to vaccine already registered in the past
It shows how to discontinue TABST
An administrative guidance
The SC accepted this exception for the 3Rs principle
Let’s look at TABST guideline in detail.
Read
Thus, TABST guidelines are kind of administrative guidance applied to the product approved previously for regulators.
The VICH SC decided to accept this exception for the name of animal welfare.
In addition, waiver of BST is entirely a decision of each government, but not the steering committee of VICH.

20. Development of BST GLs: History
2008
EU proposed harmonization of BST
SC concluded to adopt a step-wise approach
1 : TABST for inactivated vaccines (GL50)
2 : TABST for live vaccines (GL55)
3 : Laboratory Animal BST for all vaccines
BQM EWG–TABST subgroup elaborated draft GL50
2012
SC approval draft GL50 / Public consultation
2013
Final GL50 published, giving 1 year for implementation.
2014
VICH GL50 implemented
2015
The subgroup elaborated draft GL55
2016
SC approval draft GL55 / Public consultation
2017
Final GL55 published soon
This slide shows the history of BST guidelines.
(Read)

21. Categorization of BST Waiver GLs:
Animal Species
Inactivated Vaccine
Live Vaccine
Target Animals
GL50R
GL55
Laboratory Animals
On going
Currently, we are working on next guidelines for laboratory animals.
This guideline is quite similar to TABST, but include both live and inactivated vaccines.
Our expert working group is discussing on draft LABST guidelines.
I believe that LABST guidelines will be also implemented in the near future.

22. VICH guidelines for veterinary vaccines
Six guidelines have been developed exclusively for vaccines.
GCP and Pharmacovigilance GLs also cover vaccines.
Many of guidelines (e.g. quality) can be applied to vaccines.
VICH is currently working on;
Waiver of Laboratory Animal Batch Safety Testing (LABST)
Extraneous virus testing
VOF members are kindly advised to implement VICH GLs by stepwise manner according to the situation.
This is the final slide of this presentation.
We developed 6 guidelines that is exclusively for vaccines in VICH so far.
In addition to these GLs, GCP and pharmacovigilance GLs are also applied to vaccines
And I introduced development of BST waiver guidelines.
The EWG are also working on harmonization of extraneous virus testing.
Finally, I would like to introduce that VOF (Read).
That’s all I have to say in this presentation.
Thank you for your attention.

24. Taxonomy of “Biologics”
Class
Subclass
Product type
Example
Biologics
Cell/Tissue Products
Blood Products
Erythrocytes T-Cells, Monocytes, Platelets, Plasma
Somatic cells
Myocytes, Fibroblasts, Dendritic cells
Stem cells
iPS Cells, MSCs
Tissues
Cartilages, Bones, Skins, Blood vessels, Tendons, Ligaments
Nucleotide Products
Gene therapeutics
Virus /Plasmid vector, DNA Vaccine
Oligonucleotide therapeutics
SiRNA , CpG oligo, Decoy, Aptamer
Immunologicals
Anti-bodies
Antisera
Anti-tetanus serum
Immuno-globulins
Antivirus MAb
Immunogens
Vaccines
Organisms (Live, attenuated, inactivated, vector), Toxoid
Subunit/component, Peptide, DNA
Allergenics
Immunomodulators
Interferons, Interleukins
Cytomodulators
Hematopoietic factors
Erythropoietin, G-CSF
Growth factors
FGF, HGF, VEGF, NGF
Hormones
Insulin, PMSG, CG, Oxytocin, Angiotensin
Catlysers
Enzymes
TPA, lysozyme, Protease
Ribozymes
Others
Bacteriophage, probiotics, colostrum, squalene, saponin
This table shows an example of classification of Biologics.
Nowadays, biologics ort biologicals are becoming a very very large group including not only vaccine but also other many biological substances as shown here.
In order to cope with the growing biologicals, we shares the taxonomy as a first step of harmonization of the tests.

25. VICH-GL50 2. GUIDELINE 2.1. Scope 2.2. Regional Requirements
This guideline is limited to the criteria on data requirements for waiving target animal batch safety tests (TABST) of inactivated veterinary vaccines.
2.2. Regional Requirements
General batch safety testing
Current procedure for TABST in VICH region.
Other relevant requirements
Good Manufacturing Practice (GMP)
Seed lot system
Pharmacovigilance

26. VICH-GL50
2.3. Data requirements for waiving of target animal batch safety tests
Introduction
The TABST may be waived by the regulatory authority when;
a sufficient number of consecutive production batches have been produced and
comply with the tests (on specification), thus
demonstrate consistency of the manufacturing process.

27. VICH-GL50
The characteristics of the product and its manufacture
The manufacturer should demonstrate that the product is manufactured following the quality principles (e.g. seed lot system and GMP)
When other batch tests in target animals (e.g. potency tests) are conducted during the manufacturing process, it is recommended to gain additional safety data of the vaccine.

28. VICH-GL50
Information available on the current batch safety test
The manufacturer should submit batch protocol data for a sufficient number of consecutive batches (Usually 10 batches)
to demonstrate that safe and consistent production has been established.
The conduct of the TABST shall be in accordance with the regional requirements.
Variety of local and systemic reactions should be examined,
Summary and discussion should be provided.

29. VICH-GL50 2.3.1.3. Pharmacovigilance data
A pharmacovigilance system (in accordance with the VICH Guidelines) is in place during the consecutive batches were on the market.
The Data to demonstrating the consistent safe performance of the vaccine in the field should be provided.

30. VICH-GL50
Procedure for waiving the target animal batch safety test
A report should provide an overall assessment of the consistency of the product’s safety and
would include;
the number of batches manufactured,
the number of years the product has been on the market,
the number of doses sold,
the frequency and seriousness of any adverse reactions,
investigations into the causes of these adverse reactions.

31. How is GL50 implemented in Japan ?
GL50 has been implemented in Japan from Feb Applicable vaccine The vaccine which is fulfilled all of following requirements. (1) Inactivated vaccine for veterinary use. (2) More than the last 10 batches were passed the TABST. (3) Seed lot system-based product. (4) Product which is not within the re-examination period (6 years after the approval).

32. How is GL50 implemented in Japan ?
2. Application Documents
(1) Application for waiver of TABST
(2) Accompanying materials:
A. Manufacturing records (last 10 batches)
B. Batch release test data (last 10 batches)
C. Information on a defect batch (if any)
D. Revision history of the dossier
E. Rational explanation for waiving TABST (on A to D above)
F. Overall safety assessment including Pharmacovigilance data