[Title 21 CFR 630.60] [Code of Federal Regulations (annual edition) - April 1, 1996 Edition] [Title 21 - FOOD AND DRUGS] [Chapter I - FOOD AND DRUG ADMINISTRATION,] [Subchapter F - BIOLOGICS] [Part 630 - ADDITIONAL STANDARDS FOR VIRAL VACCINES] [Subpart G - Rubella Virus Vaccine Live] [Sec. 630.60 - Rubella Virus Vaccine Live.] [From the U.S. Government Publishing Office]21 FOOD AND DRUGS 7 1996-04-01 1996-04-01 false Rubella Virus Vaccine Live. 630.60 Sec. 630.60 FOOD AND DRUGS FOOD AND DRUG ADMINISTRATION, BIOLOGICS ADDITIONAL STANDARDS FOR VIRAL VACCINES Rubella Virus Vaccine Live Sec. 630.60 Rubella Virus Vaccine Live. (a) Proper name and definition. The proper name of this product shall be Rubella Virus Vaccine Live, which shall consist of a preparation of live, attenuated rubella virus. (b) Criteria for acceptable strains of attenuated rubella virus. Strains of attenuated rubella virus used in the manufacture of vaccine shall be identified by (1) historical records including origin and manipulation during attenuation and (2) antigenic specificity as rubella virus as demonstrated by tissue culture neutralization tests. (c) Extraneous agents. Seed virus used for vaccine manufacture shall be free of all demonstrable extraneous viable microbial agents except for unavoidable bacteriophage. (d) Field studies with experimental vaccines. (1) Strains used for the manufacture of Rubella Virus Vaccine Live, shall have been shown in field studies with experimental vaccines to be safe and potent in the group of individuals inoculated, which must include at least 10,000 susceptible individuals. Susceptibility shall be shown by the absence of neutralizing or hemagglutination-inhibiting antibodies against rubella virus or by other appropriate methods. (2) The virus strain used in the field studies shall be propagated in the same cell culture system that will be used in the manufacture of the product. (3) The field studies shall be so conducted that at least 5,000 of the susceptible individuals must reside when inoculated in areas where health related statistics are regularly compiled in accordance with procedures such as those used by the National Center for Health Statistics. Data in such form as will identify each inoculated person shall be furnished to the Director, Center for Biologics Evaluation and Research. (4) Inoculated persons shall be shown not to be contagious for contacts through surveillance of rubella susceptible contacts of the inoculated persons. (e) Neurovirulence safety test of the virus seed strain in monkeys-- (1) The test. A demonstration shall be made in monkeys of the lack of neurotropic properties of the seed strain of attenuated rubella virus used in the manufacture of rubella vaccine. For this purpose and to establish consistency of manufacture of the vaccine, vaccine from each of five consecutive lots shall be tested separately in monkeys shown to be serologically negative for rubella virus antibodies in the following manner: (i) A test sample of vaccine removed after clarification but before final dilution for standardization of virus content shall be used for the test. (ii) Vaccine shall be injected by combined intracerebral, intraspinal, and intramuscular routes into not less than 20 Macaca or Cercopithecus monkeys or a species found by the Director, Center for Biologics Evaluation and Research, to be equally suitable for the purpose. The animals shall be in overt [[Page 110]] good health and injected under deep barbiturate anesthesia. The intramuscular injection shall consist of 1.0 milliliter of test sample into the right leg muscles. At the same time, 200 milligrams of cortisone acetate shall be injected into the left leg muscles, and 1.0 milliliter of procaine penicillin (300,000 units) into the right arm muscles. The intracerebral injection shall consist of 0.5 milliliter of test sample into each thalamic region of each hemisphere. The intraspinal injection shall consist of 0.5 milliliter of test sample into the lumbar spinal cord enlargement. (iii) The monkeys shall be observed for 17-21 days and symptoms of paralysis as well as other neurologic disorders shall be recorded. (iv) At least 90 percent of the test animals must survive the test period without losing more than 25 percent of their weight except that, if at least 70 percent of the test animals survive the first 48 hours after injection, those animals which do not survive this 48-hour test period may be replaced by an equal number of qualified test animals which are tested pursuant to paragraphs (e)(1)(i) through (iii) of this section. At least 80 percent of the injected animals surviving beyond the first 48 hours must show gross or microscopic evidence of inoculation trauma in the thalamic area and microscopic evidence of inoculation trauma in the lumbar region of the spinal cord. If less than 70 percent of the test animals survive the first 48 hours, or if less than 80 percent of the animals meet the inoculation criteria prescribed in this paragraph, the test must be repeated. (v) At the end of the observation period, each surviving animal shall be autopsied and samples of cerebral cortex and of cervical and lumbar spinal cord enlargements shall be taken for virus recovery and identification if needed pursuant to paragraph (e)(1) (vi) of this section. Histological sections shall be prepared from both spinal cord enlargements and appropriate sections of the brain and examined. (vi) Doubtful histopathological findings necessitate (a) examination of a sample of sections from several regions of the brain in question, and (b) attempts at virus recovery from the nervous system tissues previously removed from the animal. (vii) The lot is satisfactory if the histological and other studies demonstrate no evidence of changes in the central nervous system attributable to the presence of unusual neurotropism of the seed virus or of the presence of extraneous neurotropic agents. (2) Test results. The rubella virus seed has acceptable neurovirulence properties for use in vaccine manufacture only if for each of the five lots: (i) 90 percent of the monkeys survive the observation period, (ii) the histological and other studies produce no evidence of changes in the central nervous system attributable to the presence of unusual neurotropism or replication of the seed virus and (iii) there is no evidence of the presence of extraneous neurotropic agents. (3) Need for additional neurovirulence safety testing. A neurovirulence safety test as prescribed in this paragraph shall be performed on vaccine from five consecutive lots whenever a new production seed lot is introduced or whenever the source of cell culture substrate must be reestablished and recertified as prescribed in Sec. 630.62(a), (b) and (d) of this part. [38 FR 32068, Nov. 20, 1973, as amended at 40 FR 11719, Mar. 13, 1975; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 55 FR 47876, Nov. 16, 1990]