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Archives: 1999 Session - Appendix 14

1999 Session of the Research Group of the Standing Technical Committee of EuFMD

Proposals for amendments to the FMD Monograph of the European Pharmacopoeia


Massimo Amadori
Istituto Zooprofilattico Sperimentale della Lombardia e dellÎEmilia, Brescia


The issue of a substantial revision of the FMD Monograph of the European Pharmacopoea (EP) was first raised at the 1997 Session of the Research Group of the EuFMD in Poiana-Brasov, Romania. It was stressed that the monograph was outdated in several respects and that it contained unadequate procedures. These remarks were confirmed at the 1998 Session of the Research Group in Aldershot, UK, in the framework of a general discussion which included the contributions of private vaccine producers. The recommendation of a substantial revision of the monograph was endorsed by the Executive Committee of EuFMD, and an ad hoc working group was appointed to elaborate proposals for amendments.

The main points to be dealt with can be summarised as follows:

  • The Monograph does not recognise the huge development of the Quality Assurance (QA) and in-process control procedures in the manufacturing companies.

  • The above factors actually reduce the relative importance of the controls on ready-to-use vaccines.

  • The monograph does not take into account species other than ruminants. In particular, the importance of pigs in a scenario of emergency vaccination suggests that vaccine potency may be calculated in these animals as well.

  • Some manufacturing procedures are outdated and in contrast with other existing regulations

In addition, there is a need for replacing some tests in vivo with other in vitro tests; this is prompted by the present regulations on animal welfare (EEC Directive 86/609) and also by the higher reliability of these latter in vitro tests. In fact, the tongue inoculation procedure can include very few vaccine doses; furthermore, there is uncertainty as to when the inoculation of the three vaccine doses should take place (before/after the tongue inoculation); there is also confusion between in vivo tests on bulk antigen and in vivo tests on formulated vaccine. With regard to potency, the footnote related to alternative validated tests has been omitted in the last edition and potency for pigs is not taken into account; a test in pigs may be instead mandatory in the light of the recent appearance of pig-adapted strains with little, if any pathogenicity for cattle, such as O Taiwan 1997. In general terms, the monograph was written when prophylactic vaccination was carried out in most European countries and it was influenced by the once prevailing views about disease control. Nowadays, the monograph should envisage the needs of both prophylactic and emergency vaccinations and harmonize the interests of both producers and control agencies. With regard to the latter, it is worth mentioning that the overall picture of FMD control reflected in the EP monograph is by far different from what is experienced now; with the stepwise cessation of the prophylactic vaccination in Europe; also the legal status of the FMD vaccine has been submitted to a substantial reappraisal; pressure is being exerted to apply to such a vaccine the usual licensing procedures under the control of the relevant EU agency (EMEA); in practice, the concept of an ad hoc control procedure based on the National FMD laboratories has been formally challenged (see Prof. PastoretÎs report on FMD to the European Commission). Owing to the above, the legislative framework of FMD vaccines and vaccinations is likely to be changed dramatically and a revised edition of the monograph must properly envisage such a scenario.

The Working Group on the EP monograph was formed according to the relevant recommendation of the Aldershot Session of the EuFMD Research group, later approved by the Executive Committee of the EuFMD at the Oslo meeting in November 1998. In its first meeting in Rome, in May 1999, the group worked together with invited experts, representatives of private companies and the Secretariat of EuFMD. The participants acknowledged the inappropriateness of the current FMD vaccine monograph and held a frank and open discussion to make sound proposals of amendments in line with the above-mentioned priorities and needs. A second meeting was held at Maisons-Alfort, France, in September 1999. A model document for a new monograph was prepared, which has to be transmitted to representatives of the EP Committee after approval by the Executive Committee of EuFMD. The results of these fruitful discussions are outlined hereunder; please notice that words in italics are not finalised and need further clarification and discussion.



New Monograph on FMD Vaccines


Table des matières
This was modified in line with the layout of the Quality Assurance System adopted by the manufacturers.


Safety (Detection of Residual Infectivity)
1. The in vivo test is to be omitted, and replaced by an in vitro test in a sensitive cell system.
2. The control system should be based on Quality Assurance first; then on the assessment of the inactivation kinetics and finally on safety controls of the bulk inactivated antigen.
3. Criteria for internal validation of the test on bulk inactivated antigen.
There was consensus about using an amount of antigen equal to or higher than 200 antigen doses.
There was consensus for introducing a cell susceptibility test, based on a small amount of infectious virus which has to be detected in the cell culture system which is used for safety tests.


Innocuity (tests for local and systemic tolerance)
The tests currently prescribed in the monograph under safety should be carried out during the registration procedure.
There was consensus that the procedures detailed elsewhere in the Ph. Eur. should be omitted for batch release and emergency vaccines.


New Strains
Following the appearance of new strains, these may be introduced into the existing registered vaccines without a new registration procedure.


Potency Test
Vaccine should be potency tested in cattle or in pigs.


Potency test in cattle
The potency test in cattle covers small ruminants. Not less than 1/3 of a cattle dose should be injected in small ruminants.
The standard procedure is to challenge vaccinated animals and have the results expressed as PD50. A full test is required for registration, an alternative and possibly reduced test for batch release.
The passmark for approval is at least 3 PD50 in general, whereas a potency level of at least 6 PD50 is required/strongly recommended for FMD Vaccine/Antigen banks and for the first use in non-vaccinating, FMD-free countries.
A validated alternative test may be used if correlation data with the challenge test are available.
In the framework of a Quality Assurance system and in particular in a sub-serial system of batch release, one test only is performed for the whole series of batches derived from the same bulk of inactivated antigen.
Furthermore, in the framework of a Quality Assurance system, the producer is allowed to show consistency of potency results for a particular vaccine strain in at least 3 representative vaccine production batches. In this case, the following batches may be released after a proven serological response in vaccinated animals.


Challenge Test in Pigs
Use pigs not less than 2 months old obtained from areas free from foot-and-mouth disease, which have never been vaccinated against foot-and-mouth disease and are free from antibodies against the different types of foot-and-mouth disease virus. Vaccinate not fewer than three groups of not fewer than five pigs per group by the route stated on the label. House the control and the test animals in separate isolated units. Use a different dose of the vaccine for each group. Administer the different doses by injecting different volumes of the vaccine as described above for cattle. Three to four weeks after the vaccination, challenge the vaccinated animals and a control group of two animals into one heel bulb with a suspension of virus obtained from pigs, which is sufficient to induce generalised disease in the control animals (e.g. 1,000 TCID50), but without producing conditions of overwhelming challenge. Remove vaccinated animals as soon as they show vesicular lesions on sites other than the injection site. Slaughter animals after eight days. Protected animals may only display local lesions at the injection site. The test is not valid unless each control animal shows lesions on at least three feet. From the number of protected animals in each group, calculate the PD50 content of the vaccine. The passmark for approval is at least 3 PD50 in general, whereas a potency level of at least 6 PD50 is required/strongly recommended for FMD Vaccine/Antigen banks and for the first use in non-vaccinating, FMD-free countries.


FMD vaccines should be produced according to the principles of GMP as recommended by the OIE Manual (Chapter 1.6), 1996 edition and as specified in the current relevant European Union Directive(s).


Virus inactivation should be carried out by a two-tank system as described under GMP principles by means of 1st order inactivants.


Inactivation procedure
(as in current monograph)


Tests on Bulk Inactivated Antigen
(as in current monograph)





The above proposals indicate practical solutions to the main problems and concerns raised by the present edition of the EP monograph, as outlined in the introductory remarks. It is obviously a reasonable compromise between the different needs of vaccine consumers and producers, which acknowledges the dramatic changes of the FMD vaccine policy in Europe. As far as possible, the model document approved attains to the present layout of the EP monograph and just highlights the possible points of revision. The main novel features proposed can be summarised as follows:

  • A internal validation procedure for the safety test on bulk antigen.

  • strong reduction of the in vivo tests and, in particular, of the challenge of vaccinated animals in a dynamic link with the Quality Assurance System.

  • The distinction between tests needed for licensing and those needed for batch release.

  • A challenge test in pigs.

  • A reference to the Good Manufacturing Practices.

The most controversial issue is probably the passmark for vaccine approval: 3 or 6 PD50 ? As a matter of fact, the monograph has to recognise the dramatic improvements of the manufacturing techniques which allow for the preparation of very potent vaccines against a large array of FMDV strains. Furthermore, it is arguable that the present system of injection of variable vaccine volumes instead of vaccine dilutions in neutral buffer can give rise to artificially higher PD50 values , i. e. 3 PD50 obtained with injection of variable vaccine volumes would correspond to 2.2 PD50 after vaccine dilution in neutral buffer; in practice, the previous figure would be reached with the existing system at a level of 4.5 PD50 (see Stellmann et al., 1977, Arch. Virol. 54, 61-74). Finally, to my knowledge, the current contracts of sale to FMD vaccine banks usually refer to a passmark of 6 PD50. On the other hand, the producers argue that too strong an emphasis on potency may induce in several Countries an overconfidence on this latter feature to the detriment of other aspects of paramount importance for disease control; because of the higher cost of vaccines, such a requirement might prompt to a reduced usage of FMD vaccines and negative repercussions might then ensue.




List of the participants in the discussion

Members of the working Group
K. De Clercq ( Chairman of the Research Group of EuFMD)
M. Amadori
S. Barteling
B. Haas


R. Ahl ( Representative of the EC Scientific Veterinary Committee)
Prof. G. F. Panina ( Representative of the EC Scientific Veterinary Committee)
P. Barnett (IAH, Pirbright)


Representatives of Private companies

Doel ( Mçrial)
H. Roedder ( Bayer)
A. J. Breeuwsma (Intervet)


Secretariat EuFMD
Y. Leforban ( Secretary)
J. Ryan (APO)