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The W.H.O. international laboratory for biological standards, Weybridge, England
Journal of Biological Standardization 1973 1, 371-374
The W.H.O. international laboratory for biological standards, Weybridge, England.* E. C. H&se,? I. Davidsonf and B. J S’hreevet
The need for the establishment of an international system of biological standards was recognized by the Health Organization of the League of Nations after the First World War and two laboratories were designated to undertake the work of establishing standards for medical use ; these were the Statens Seruminstitut in Copenhagen, which was given charge of the immunological standards, and the National Institute for Medical Research in London where the pharmacological standards were housed. After the Second World War the World Health Organization continued with and developed the work of international biological standardization and considerable progress was made in this field. In veterinary medicine progress was somewhat slower possibly because the pharmaceutical industries in the developed countries had not made such rapid advances in the production of veterinary products as had been accomplished in the field of human medicine. Nevertheless, in conjunction with the International Office of Epizootics, a standard for Brucella abortus serum was established in 1933 and this serum has been distributed on an international basis since 1937. Further developments did not, however, occur until well after the conclusion of the Second World War. The importance of Brucellosis as a zoonotic disease had long been recognized and in 1952 the Expert Committee on Biological Standardization of the World Health Organization (W.H.O. Expert Committee on Biological Standardization, 1952) established the O.I.E. Brucella abortus serum as an international biological standard; this substance was, therefore, the first veterinary biological substance to be established as an international standard. It became evident that there was a growing need for the establishment of veterinary international biological standards and the W.H.O. Committee on Biological Standards, encouraged by the 16th World International Veterinary Congress at Madrid, agreed to * Received for publication t Ministry of Agriculture, Surrey, England.
8 May 1973. Fisheries and Food,
Central
Veterinary
Laboratory,
Weybridge,
371
W.H.O.
BIOLOGICAL
STANDARDS
LABORATORY
“the expansion of the Committee’s work particularly in respect of substances of veterinary importance” and recommended that the Food and Agricultural Organization “be consulted concerning the possibility of nominating a Third International Laboratory for Biological Standards with the responsibility for custody and distribution of those international standards and international reference preparations that were primarily of veterinary importance”. In October 1961, therefore, the World Health Organization, with the support of the Food and Agricultural Organization, invited Her Majesty’s Government, through the Ministry of Health, to agree that the Central Veterinary Laboratory at Weybridge should be designated as the Third International Laboratory for Biological Standards. This high honour was accepted and the International Laboratory was established within the organization of the Biological Products and Standards Department at Weybridge in September 1962. The Laboratory undertakes the preparation, storage and world-wide distribution of W.H.O. international biological standards that are primarily of veterinary importance. It is responsible for the renewal of the various standard preparations when stocks of these preparations are becoming exhausted. It carries out research work entrusted to it by W.H.O. upon the existing standard preparations and undertakes studies on the preparation of other substances of veterinary importance as international standards. Selected workers from National Laboratories for Biological Standards are accepted from time to time by the International Laboratory for limited periods to study bioassay procedures used in this type of work. It is required to supply on request samples of International Standards or International Reference Preparations or International Reference Reagents, to National Laboratories for Biological Standards or to other Biological Substances Laboratories in those countries where National Laboratories do not exist. The following International Standards and Reference Preparations are presently held and distributed by the Third International Laboratory for Biological Standards at Weybridge (Table 1). In addition to the preparations mentioned in the Table, proposed international standards for anti-Salmonellapullorum sera have been produced against the two important antigenic types of S. pullorum. These sera, which are to be used for standardizing the pullorum agglutination test, have undergone a collaborative assay and the results await consideration by the World Health Organization Expert Committee on Biological Standardizationl. A collaborative assay is in progress to test the suitability of proposed international standards for Clostridium welchii beta and epsilon toxoids and a study has also been undertaken to compare the complement-fixing activities of the first and second International Standards for Anti-Br. abortus Serum. These latter preparations were originally established for measuring agglutinating activity and the recent exercise was performed to determine whether an international unit of complement-fixing activity might be defined. A proposed international reference preparation for Rinderpest Cell Culture Vaccine is undergoing safety tests and the need for a bovine tuberculin standard is being considered. The Laboratory has made a considerable contribution to the work of the World Health Organization by providing expert advice in the formulation of the following international requirements for the manufacture and control of biological substances of use either in human or veterinary medicine or in both. (a) Requirements for Anthrax Spore Vaccine (live-for veterinary use) (W.H.O., 1967) (Requirements for Biological Substances No. 13). 1 Established
372
as International
Standards
by the Committee
in April,
1973.
Substance
oedematiens
B
serum
gall&f+
Other Preparations: Anthrax Staphylococcus beta antitoxin
ANTIBIOTICS Tylosin Hygromycin Nisin
Anti-swine-fever
ticum serum
Anti-Mycoplasma
of dried
bovine
hyperimmune
mg of freeze-dried
68.5 mg
95.52
i.u./
serum
(1000
horse
serum
containing containing containing
17JB (challenge strain). discontinued in 1956)).
l?rysipelothrix
40 mg of tylosin base (1000 i.u./mg) 40 mg of hygromycin B (1120 i.u./mg) 85 mg of nisin (1000 i.u./mg)
spore vaccine strain 34F2. Anthrax strain (working standard (International Standard
0.001 0.0008928 0ao1
0.89
0.0556
0.0897
0.14
Ampoules Ampoules Ampoules
1963
1st Standard
1954 1967 1967
1st Standard 1st Standard 1st Standard
type
N strain
1st Standard 1966 1st Standard 1966 1 st Reference Preparation 1969
1 st Reference Preparation 1966 1 st Reference Preparation 1969 1st Standard 1963
1954
1967 1954
2kl”~~~fic%d 1st Standard 1st Standard
1952
1st Standard
1st Reference Preparation 1967 1st Reference Preparation 1966
1959
1st Standard
Years of establishment (unitage of previous standards)
rhusioputhiae
Ampoules containing 65.7 mg of dried hyperimmune horse serum (1000 i.u./ampoule) Ampoules containing 87.9mg of dried hyperimmune horse serum (628 i.u./ampoule) Ampoules containing 89.7 mg of freeze-dried hyperimmune horse serum (1000 i.u./ampoule) Ampoules containing 79.6 mg of freeze-dried hyperimmune horse serum (1000 i.u./ampoule) Ampoules containing 55.5 mg of freeze-dried chicken serum (320 i.u./ ampoule) Ampoules containing 55.6 mg of freeze-dried chicken serum (1000 i.u./ ampoule) Ampoules containing 889.5 mg of freeze-dried pig strum (1000 i.u./ ampoule)
Ampoules containing ampoule)
0.0657
0.1734
se-
dispensed
Ampoules containing (5000 i.u./ampoule)
Anti-Newcastle-disease
serum
in which
Ampoules containing 499 mg of dried vaccine derived from formaldehyde-treated Erysipelothrix rhusiopathiue type B, adsorbed to aluminium hydroxide (1000 i.u./ampoule) Ampoules containing 525 mg of freeze-dried vaccine derived from formaldehyde-treated allantoic fluid of eggs infected with strains of Newcastle disease virus adsorbed to aluminium hydroxide (525 i.u./ ampoule) Ampoules containing 109.5 mg of freeze-dried allantoic fluid derived from eggs infected with the virus (Hitchner B, strain) Ampoules containing 53.4 mg of freeze-dried toxoid
Form
TABLE 1.
0.0137
0.0796
welchii (per-
Clostridium
-
-
0.09552
I.0
0.50
fringens) type B antitoxin CL. welchii (perfringens) type D antitoxin Swine erysipelas serum (anti-N) Anti-canine-distemper serum Anti-canine-hepatitis
abortus
toxoid
Anti-Brucella serum
ANTIBODIES
(alpha)
Cl%%ma
vaccine
Newcastle
disease
vaccine
vaccine
Newcastle disease (inactivated)
ANTIGENS Swine erysipelas
International unit of present standard (mid
Germany
West
Kingdom
Kingdom
Kingdom
Kingdom
strain).
States States Kingdom
Kingdom
Kingdom
Germany
Kingdom
Kingdom
Germany
(challenge
United United United
United
United
West
United
United
West
United
United
United
United
Netherlands
Germany
of origin
West
Country
W.H.O.
BIOLOGICAL
STANDARDS
LABORATORY
(b) Requirements for Tuberculins (W.H.O., 1968) (Requirements for Biological Substances No. 16). (c) Requirements for Rinderpest Cell Culture Vaccine (live) and Rinderpest Vaccine (live) (W.H.O., 1970) (Requirements for Biological Substances No. 19). (d) Requirements for Bruce&z abortus Strain 19 Vaccine (live-for veterinary use) (W.H.O., 1970) (R equirements for Biological Substances No. 20). The requirements for Rinderpest Cell Culture Vaccine have stimulated the need for the International Reference Preparation for this vaccine mentioned above; similarly the Anthrax Spore Vaccine Requirements led to the establishment of the vaccine and challenge reference strain referred to in the Table. Requirements for the manufacture and control of B. m&en& Rev I vaccine and foot-and-mouth disease vaccine are in the course of preparation. The Laboratory is also involved in the preparation of British Biological Standards for use in control work specified by the British Veterinary Codex Supplement, 1970 and the Medicines Act, 1968; these British Standards are available for international use. Standards exist for anti-Newcastle-disease serum, anti-chicken-influenza A serum and virginiamycin. A standard for Marek’s disease vaccine has recently been prepared for assessing the virus content of commercial turkey herpes virus vaccines and is under test at the present time. As a result of satisfactory accelerated degradation studies on a standard for avian infectious bronchitis vaccine an international collaborative assay is being organized, and a multicomponent clostridial vaccine is currently under test. Consideration is being given to the production of standards for the European Pharmacopoeia Commission and future work may also include the preparation of Research Standards such as specific immunoglobulins of animal origin. REFERENCES W.H.O. Expert Committee on Biological Standardization (1952). World Health Orgunizution, Technical Report Series 1953, 68, 9. World World World World
374
Health Health Health Health
Organization Organization Organization Organization
Technical Technical Technical Technical
Report Report Report Report
Series 1967, 361, 31-40. Series 1968, 384, 23-41. Series 1970, 444, 23-57.
Series 1970, 444, 58-70.
The W.H.O. international laboratory for biological standards, Weybridge, England.* E. C. H&se,? I. Davidsonf and B. J S’hreevet
The need for the establishment of an international system of biological standards was recognized by the Health Organization of the League of Nations after the First World War and two laboratories were designated to undertake the work of establishing standards for medical use ; these were the Statens Seruminstitut in Copenhagen, which was given charge of the immunological standards, and the National Institute for Medical Research in London where the pharmacological standards were housed. After the Second World War the World Health Organization continued with and developed the work of international biological standardization and considerable progress was made in this field. In veterinary medicine progress was somewhat slower possibly because the pharmaceutical industries in the developed countries had not made such rapid advances in the production of veterinary products as had been accomplished in the field of human medicine. Nevertheless, in conjunction with the International Office of Epizootics, a standard for Brucella abortus serum was established in 1933 and this serum has been distributed on an international basis since 1937. Further developments did not, however, occur until well after the conclusion of the Second World War. The importance of Brucellosis as a zoonotic disease had long been recognized and in 1952 the Expert Committee on Biological Standardization of the World Health Organization (W.H.O. Expert Committee on Biological Standardization, 1952) established the O.I.E. Brucella abortus serum as an international biological standard; this substance was, therefore, the first veterinary biological substance to be established as an international standard. It became evident that there was a growing need for the establishment of veterinary international biological standards and the W.H.O. Committee on Biological Standards, encouraged by the 16th World International Veterinary Congress at Madrid, agreed to * Received for publication t Ministry of Agriculture, Surrey, England.
8 May 1973. Fisheries and Food,
Central
Veterinary
Laboratory,
Weybridge,
371
W.H.O.
BIOLOGICAL
STANDARDS
LABORATORY
“the expansion of the Committee’s work particularly in respect of substances of veterinary importance” and recommended that the Food and Agricultural Organization “be consulted concerning the possibility of nominating a Third International Laboratory for Biological Standards with the responsibility for custody and distribution of those international standards and international reference preparations that were primarily of veterinary importance”. In October 1961, therefore, the World Health Organization, with the support of the Food and Agricultural Organization, invited Her Majesty’s Government, through the Ministry of Health, to agree that the Central Veterinary Laboratory at Weybridge should be designated as the Third International Laboratory for Biological Standards. This high honour was accepted and the International Laboratory was established within the organization of the Biological Products and Standards Department at Weybridge in September 1962. The Laboratory undertakes the preparation, storage and world-wide distribution of W.H.O. international biological standards that are primarily of veterinary importance. It is responsible for the renewal of the various standard preparations when stocks of these preparations are becoming exhausted. It carries out research work entrusted to it by W.H.O. upon the existing standard preparations and undertakes studies on the preparation of other substances of veterinary importance as international standards. Selected workers from National Laboratories for Biological Standards are accepted from time to time by the International Laboratory for limited periods to study bioassay procedures used in this type of work. It is required to supply on request samples of International Standards or International Reference Preparations or International Reference Reagents, to National Laboratories for Biological Standards or to other Biological Substances Laboratories in those countries where National Laboratories do not exist. The following International Standards and Reference Preparations are presently held and distributed by the Third International Laboratory for Biological Standards at Weybridge (Table 1). In addition to the preparations mentioned in the Table, proposed international standards for anti-Salmonellapullorum sera have been produced against the two important antigenic types of S. pullorum. These sera, which are to be used for standardizing the pullorum agglutination test, have undergone a collaborative assay and the results await consideration by the World Health Organization Expert Committee on Biological Standardizationl. A collaborative assay is in progress to test the suitability of proposed international standards for Clostridium welchii beta and epsilon toxoids and a study has also been undertaken to compare the complement-fixing activities of the first and second International Standards for Anti-Br. abortus Serum. These latter preparations were originally established for measuring agglutinating activity and the recent exercise was performed to determine whether an international unit of complement-fixing activity might be defined. A proposed international reference preparation for Rinderpest Cell Culture Vaccine is undergoing safety tests and the need for a bovine tuberculin standard is being considered. The Laboratory has made a considerable contribution to the work of the World Health Organization by providing expert advice in the formulation of the following international requirements for the manufacture and control of biological substances of use either in human or veterinary medicine or in both. (a) Requirements for Anthrax Spore Vaccine (live-for veterinary use) (W.H.O., 1967) (Requirements for Biological Substances No. 13). 1 Established
372
as International
Standards
by the Committee
in April,
1973.
Substance
oedematiens
B
serum
gall&f+
Other Preparations: Anthrax Staphylococcus beta antitoxin
ANTIBIOTICS Tylosin Hygromycin Nisin
Anti-swine-fever
ticum serum
Anti-Mycoplasma
of dried
bovine
hyperimmune
mg of freeze-dried
68.5 mg
95.52
i.u./
serum
(1000
horse
serum
containing containing containing
17JB (challenge strain). discontinued in 1956)).
l?rysipelothrix
40 mg of tylosin base (1000 i.u./mg) 40 mg of hygromycin B (1120 i.u./mg) 85 mg of nisin (1000 i.u./mg)
spore vaccine strain 34F2. Anthrax strain (working standard (International Standard
0.001 0.0008928 0ao1
0.89
0.0556
0.0897
0.14
Ampoules Ampoules Ampoules
1963
1st Standard
1954 1967 1967
1st Standard 1st Standard 1st Standard
type
N strain
1st Standard 1966 1st Standard 1966 1 st Reference Preparation 1969
1 st Reference Preparation 1966 1 st Reference Preparation 1969 1st Standard 1963
1954
1967 1954
2kl”~~~fic%d 1st Standard 1st Standard
1952
1st Standard
1st Reference Preparation 1967 1st Reference Preparation 1966
1959
1st Standard
Years of establishment (unitage of previous standards)
rhusioputhiae
Ampoules containing 65.7 mg of dried hyperimmune horse serum (1000 i.u./ampoule) Ampoules containing 87.9mg of dried hyperimmune horse serum (628 i.u./ampoule) Ampoules containing 89.7 mg of freeze-dried hyperimmune horse serum (1000 i.u./ampoule) Ampoules containing 79.6 mg of freeze-dried hyperimmune horse serum (1000 i.u./ampoule) Ampoules containing 55.5 mg of freeze-dried chicken serum (320 i.u./ ampoule) Ampoules containing 55.6 mg of freeze-dried chicken serum (1000 i.u./ ampoule) Ampoules containing 889.5 mg of freeze-dried pig strum (1000 i.u./ ampoule)
Ampoules containing ampoule)
0.0657
0.1734
se-
dispensed
Ampoules containing (5000 i.u./ampoule)
Anti-Newcastle-disease
serum
in which
Ampoules containing 499 mg of dried vaccine derived from formaldehyde-treated Erysipelothrix rhusiopathiue type B, adsorbed to aluminium hydroxide (1000 i.u./ampoule) Ampoules containing 525 mg of freeze-dried vaccine derived from formaldehyde-treated allantoic fluid of eggs infected with strains of Newcastle disease virus adsorbed to aluminium hydroxide (525 i.u./ ampoule) Ampoules containing 109.5 mg of freeze-dried allantoic fluid derived from eggs infected with the virus (Hitchner B, strain) Ampoules containing 53.4 mg of freeze-dried toxoid
Form
TABLE 1.
0.0137
0.0796
welchii (per-
Clostridium
-
-
0.09552
I.0
0.50
fringens) type B antitoxin CL. welchii (perfringens) type D antitoxin Swine erysipelas serum (anti-N) Anti-canine-distemper serum Anti-canine-hepatitis
abortus
toxoid
Anti-Brucella serum
ANTIBODIES
(alpha)
Cl%%ma
vaccine
Newcastle
disease
vaccine
vaccine
Newcastle disease (inactivated)
ANTIGENS Swine erysipelas
International unit of present standard (mid
Germany
West
Kingdom
Kingdom
Kingdom
Kingdom
strain).
States States Kingdom
Kingdom
Kingdom
Germany
Kingdom
Kingdom
Germany
(challenge
United United United
United
United
West
United
United
West
United
United
United
United
Netherlands
Germany
of origin
West
Country
W.H.O.
BIOLOGICAL
STANDARDS
LABORATORY
(b) Requirements for Tuberculins (W.H.O., 1968) (Requirements for Biological Substances No. 16). (c) Requirements for Rinderpest Cell Culture Vaccine (live) and Rinderpest Vaccine (live) (W.H.O., 1970) (Requirements for Biological Substances No. 19). (d) Requirements for Bruce&z abortus Strain 19 Vaccine (live-for veterinary use) (W.H.O., 1970) (R equirements for Biological Substances No. 20). The requirements for Rinderpest Cell Culture Vaccine have stimulated the need for the International Reference Preparation for this vaccine mentioned above; similarly the Anthrax Spore Vaccine Requirements led to the establishment of the vaccine and challenge reference strain referred to in the Table. Requirements for the manufacture and control of B. m&en& Rev I vaccine and foot-and-mouth disease vaccine are in the course of preparation. The Laboratory is also involved in the preparation of British Biological Standards for use in control work specified by the British Veterinary Codex Supplement, 1970 and the Medicines Act, 1968; these British Standards are available for international use. Standards exist for anti-Newcastle-disease serum, anti-chicken-influenza A serum and virginiamycin. A standard for Marek’s disease vaccine has recently been prepared for assessing the virus content of commercial turkey herpes virus vaccines and is under test at the present time. As a result of satisfactory accelerated degradation studies on a standard for avian infectious bronchitis vaccine an international collaborative assay is being organized, and a multicomponent clostridial vaccine is currently under test. Consideration is being given to the production of standards for the European Pharmacopoeia Commission and future work may also include the preparation of Research Standards such as specific immunoglobulins of animal origin. REFERENCES W.H.O. Expert Committee on Biological Standardization (1952). World Health Orgunizution, Technical Report Series 1953, 68, 9. World World World World
374
Health Health Health Health
Organization Organization Organization Organization
Technical Technical Technical Technical
Report Report Report Report
Series 1967, 361, 31-40. Series 1968, 384, 23-41. Series 1970, 444, 23-57.
Series 1970, 444, 58-70.