recommendations to assure the quality, safety and efficacy of tetanus vaccines
TRANSCRIPT
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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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TERMINOLOGY
0Working 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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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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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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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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Part A. Manufacturing recommendations
0A.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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Part A. Manufacturing recommendations
0A.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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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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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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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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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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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
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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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
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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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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A.6 Records
Good manufacturing practices: main principles for pharmaceutical products
Good manufacturing practices for biological products
0Written records should be kept of all tests, irrespective of their results.
0The records should be of a type from which annual trends can be determined.
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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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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
A.9 Distribution and transport
0The requirements given in:
Good manufacturing practices: main principles for pharmaceutical products
Good manufacturing practices for biological products should apply
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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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SEPAS
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