Recommendations to assure the quality, safety and efficacy of tetanus vaccines

1. Aref farrokhi
aarreeff@ymail.com
Reference: WHO-TRS
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3. ‫پست‬ ‫بايد‬ ‫زيست‬ ‫سان‬ ‫بدين‬ ‫گر‬
‫نياويزم‬ ‫رسوائی‬ ‫به‬ ،‫را‬ ‫عمرم‬ ‫فانوس‬ ‫اگر‬ ‫شرمم‬ ‫بی‬ ‫چه‬ ‫من‬
‫بست‬ ‫بن‬ ‫کوچه‬ ِ‫خشک‬ ِ‫کاج‬ ِ‫د‬‫بلن‬ ‫بر‬
‫پاک‬ ‫بايد‬ ‫زيست‬ ‫سان‬ ‫بدين‬ ‫گر‬
،‫کوه‬ ‫چون‬ ‫خود‬ ‫ايمان‬ ‫از‬ ‫ننشانم‬ ‫اگر‬ ‫ناپاکم‬ ‫چه‬ ‫من‬
‫خاک‬ ‫بقای‬ ‫بی‬ ‫تراز‬ ‫بر‬ ‫جاودانه‬ ‫يادگاری‬...‫شاملو‬
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4. TERMINOLOGY
0Master seed lot
A quantity of bacterial suspension that is derived from a single strain.
Has a uniform composition.
It is used for inoculating media for preparation of the working seed lot.
The master seed lot should be stored as a frozen stock or as a lyophilized
stock at a temperature known to ensure stability.
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5. TERMINOLOGY
0 Working seed lot
0 A bacterial culture derived from the master seed lot.
0 The working seed lot should be prepared from the master seed
lot by as few cultural passages as possible, having the same
characteristics as the master seed lot and intended for
inoculating media for the preparation of single harvests.
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6. TERMINOLOGY
0 Seed lot
A quantity of bacterial suspension that is derived from one strain,
is used for preparing the inoculum for the production medium.
0 Single harvest
The toxic filtrate or toxoid obtained from one batch of cultures
inoculated, harvested and processed together.
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7. TERMINOLOGY
0 Bulk purified toxoid
The processed purified material, prepared from either a single
harvest or a pool of a number of single harvests. It is the parent
material from which the final bulk is prepared.
0 Final bulk
The homogeneous final vaccine present in a single container from
which the final containers are filled either directly or through one
or more intermediate containers.
0 Final lot
A collection of sealed final containers that is homogeneous in all
respects. In principle, a final lot must therefore have been filled and
further processed (e.g. freeze-dried) from a single final bulk
container in one continuous working session.
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8. Key standards used in the control
of tetanus vaccines
The fourth International Standard for Tetanus Toxoid, Adsorbed
The second International Standard of Tetanus Toxoid for Flocculation
The first International Standard for Tetanus Immunoglobulin
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9. Part A. Manufacturing
recommendations
0 A.1 Definitions
 A.1.1 International name and proper name :“tetanus vaccine adsorbed”
 A.1.2 Descriptive definition :
Tetanus vaccine adsorbed is a preparation of tetanus toxoid prepared by treating
tetanus toxin by chemical means to render it nontoxic without losing its
immunogenic potency.
The toxoid is adsorbed onto, or precipitated with, a suitable adjuvant.
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10. Part A. Manufacturing
recommendations
0 A.2 General manufacturing recommendations
0 Good manufacturing practices: main principles for pharmaceutical
products
0 Good manufacturing practices for biological products
0 This includes demonstration of the purity and quality of the
production strain and seed lots, in-process control testing, testing
for process additives and process intermediates, and the
development and establishment of lot release tests.
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11. Part A. Manufacturing
recommendations
0A.3 Production, processing and control
 A.3.l Production precautions
 A.3.2 Production strain and seed lots
 A.3.3 Single harvests
 A.3.4 Bulk purified toxoid
 A.3.5 Final bulk
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12. A.3.2 Production strain and seed lots
 A.3.2.1 Strains of Clostridium tetani
 A.3.2.2 Seed lot system
1. multilocus enzyme electrophoresis (MEE),
2. matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF)
3. mass spectrometry
4. pulsed-field gel electrophoresis (PFGE)
5. multiple-locus sequencing typing (MLST)
6. restriction fragment length polymorphism (RFLP) analysis
 A.3.2.3 Culture medium for production of toxin
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13. A.3.3 Single harvests
 A.3.3.1 Control of bacterial purity
 A.3.3.2 Filtration
 A. 3.3.3 Determination of crude toxin concentration
 Manual for the production and control of vaccines: tetanus toxoid
 The WHO manual for quality control of diphtheria, tetanus and pertussis vaccines
 A.3.3.4 Detoxification and purification
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14. A.3.4 Bulk purified toxoid
A.3.4.1 Preparation
A.3.4.2 Sterility
General requirements for the sterility of biological substances (Requirements for
biological substances No. 6, revised 1973, amendment 1995)
A.3.4.3 Antigenic purity
A.3.4.4 Specific toxicity
WHO manual for quality control of diphtheria, tetanus and pertussis vaccines
A.3.4.5 Reversion to toxicity
A.3.4.6. Storage of bulk purified toxoid
WHO’s Guidelines on stability evaluation of vaccines
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15. A.3.4.3 Antigenic purity
Each bulk purified toxoid should be tested for antigenic strength and
purity by determining the antigen concentration in Lf units and the
concentration of protein (nondialyzable) nitrogen.
 Manual for the production and control of vaccines: tetanus toxoid
 WHO manual for quality control of diphtheria, tetanus and pertussis
vaccines.
Physicochemical analysis, using methods such as SDS-PAGE and HPLC,
may be used to monitor antigenic purity and to provide additional
information on antigen integrity and the extent of aggregation and
proteolysis.
These additional characterization tests should be performed whenever a
new working seed is introduced.
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A.3.4 Bulk purified toxoid

16. A.3.5 Final bulk
A.3.5.1 Preparation
WHO’s Guidelines on regulatory expectation related to the elimination,
reduction or replacement of thiomersal in vaccines should be followed
A.3.5.2 Control tests
WHO Manual for quality control of diphtheria, tetanus and pertussis
vaccines
A.3.5.3 Storage of final bulk
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17. A.3.5.2 Control tests
• A3.5.2.1 Preservative
• A.3.5.2.2 Adjuvants
• A.3.5.2.3 Degree of adsorption
WHO Manual for quality control of diphtheria, tetanus and pertussis vaccines
• A.3.5.2.4 Sterility
General requirements for the sterility of biological substances (Requirements for biological
substances No. 6, revised 1973, amendment 1995)
• A.3.5.2.5 Specific toxicity
• A.3.5.2.6 Potency
WHO manual for quality control of diphtheria, tetanus and pertussis vaccines
• A.3.5.2.7 Amount of residual free detoxifying agent
• A.3.5.2.8 pH
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A.3.5 Final bulk

18. A.4 Filling and containers
 Good manufacturing practices: main principles for pharmaceutical products
 Good manufacturing practices for biological products
0 Single-dose or multiple-dose containers may be used.
0 Vaccines in multidose containers should contain a suitable
antimicrobial preservative .
0 The filling process should be suitably validated by comparison of key
parameters measured in the final bulk and the final lot. Such studies
should include measurement of the degree of adsorption.
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19. A.5 Control of final product
A.5.1 Identity
A.5.2 Sterility
A.5.3 Potency
A.5.4 Innocuity
A.5.5 Adjuvant content
A.5.6 Degree of adsorption
A.5.7 Preservative content
0 A.5.8 pH
0 A.5.9 Extractable volume
0 A.5.10 Inspection of final containers
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20. A.6 Records
 Good manufacturing practices: main principles for pharmaceutical products
 Good manufacturing practices for biological products
0 Written records should be kept of all tests, irrespective of
their results.
0 The records should be of a type from which annual trends
can be determined.
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21. A.7 Samples
The recommendations given in Good
manufacturing practices: main principles for
pharmaceutical products and Good
manufacturing practices for biological products ,
should apply.
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22. A.8 Labeling
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1. the words “Tetanus Vaccine Adsorbed” and/or the proper name of the product
2. the licence number of the product
3. the name of the manufacture
4. the number of the final lot
5. the identity of any preservative or adjuvant
6. the amount of antigen in Lf and/or minimum potency in IU per SHD
7. the recommended storage temperature and the expiry date if kept at that temperature
8. the recommended SHD and the route of administration
9. the statement that the vaccine satisfies the requirements of this document
10. the address of the manufacturer
11. the recommended temperature for transport
12. a warning that the adsorbed vaccine should not be frozen
13. a warning that the adsorbed vaccine should be shaken before use
14. instructions for the use of the vaccine, and information on contraindications and the reactions
that may follow vaccination

23. A.9 Distribution and transport
0 The requirements given in:
 Good manufacturing practices: main principles for pharmaceutical
products
 Good manufacturing practices for biological products should apply
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24. A.10 Stability, storage and expiry
date
0 A.10.1 Stability :
WHO’s Guidelines on stability evaluation of vaccines
the vaccine should meet the requirements for final product at expiry date for sterility,
potency, adjuvant content, degree of adsorption, preservative content, pH and
extractable volume, where applicable
0 A.10.2 Storage conditions
0 A.10.3 Expiry date
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25. SEPAS
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