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Testing Antivenoms - Quality Control of Antivenoms in Japan

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Testing Antivenoms - Quality Control of Antivenoms in Japan Testing antivenoms - Quality control of antivenoms in Japan - Motohide TAKAHASHI, Ph.D Yoshichika ARAKAWA, MD, Ph.D Deptartment of Bacterial Pathogenesis and Infection Control National Institute of Infectious Diseases Tokyo, Japan ;Japanese Mamushi < Gloydius blomhoffii or Korean Mamushi ;Chinese Mamushi < Gloydius blomhoffii brevicaudus Gloydius blomhoffii (Mamushi) Gloydius blomhoffii and its subspecies were proposed to be regrouped from Agkistrodon halys in 1997. (W Wüster et al., Toxicon,1997) Gloydius blomhoffii and its subspecies contain at least two well characterized toxins, lethal toxin and hemorrhagic toxin. Bite injury by mamushi (outside of right foot) Two bite traces ) appear about 1.5 cm distance. Total length of snake body was 56cm (larger than middle size). Supply sources of Mamushi antivenom products in each country Japan : domestically produced by KAKETSUKEN China : domestically produced by SIBP Korea : imported from China and Japan Kinds of Antivenom/antitoxin (Equine) in Japan Products* Antigen for horse-immunizing Marketing quantity (approximately) Snake venom 3,000 vials/year Mamushi antivenom Gloydius blomhoffii Snake venom 200 vials/year Habu antivenom Protobothroዄps flavoviridis Gas gangrene antitoxin Bacterial toዅxin genus 2,000 vials/5 years Clostridium ዄ Botulism antitoxin Bacterial toዅxin genus 200 vials/5 years type A, B, E, & F Clostridium ዄ Botulism antitoxin Bacterial toዅxin genus 300 vials/5 years type E Clostridium ዄ Diphtheria antitoxin Bacterial toxin ዅgenus 1,000 vials/5 years ዆ Corynebacterium All the products are manufactured by KAKETSUKEN. Flow sheet of Freeze-dried Mamushi Antivenom product Manufacturing process Operating procedure Healthy horse Equine infectious anaemia virus et al Venom-injection Tetanus toxoid Blood collection Whole blood collection, serum centrifugation Crude antivenom material Dilution, pH-adjustment Digestion by pepsin Purification pH-adjustment Salting-out Dialysis Dialysis, pH-adjustment Aseptic filtration Bulk material Addition of solution Addition of stabilizer, dilution Aseptic filtration Final bulk Filling Filling Lyophilizatuion, Sealing Lyophilization, Sealing Final product Packaging Characterization of the Freeze-dried Mamushi Antivenom, Equine Item* ៑ Freeze-dried Mamushi Antivenom Moisture content( 3%) pass(0.17%) pH (6.8-7.4) pass(7.07) Protein content(<30 mg/300U) pass(17.3 mg/300U) Sterility pass Test for freed៑om frᚴom abnormal toxicity pass ᚴ Pyrogen test( 1.3 ) pass(0.14 ) Pᮦotency test ្ ᮦAnti-lethal toxin titer( 3្00 U/mL) pass (400 U/mL) ᯚAnti-haemorrhagic titer( 300 U/mL) pass(300 U/mL) Minimum Requirement of Biological Products in Japan. Preparation of a regional reference standard for mamushi (Gloydius blomhoffii) antivenom in cooperation with Korea, China, and Japan Background Mamushi snakes (Gloydius blomhoffii) that produce very similar venoms inhabit in a very wide geographical area including Japan, Korea and China continent. Antivenoms has been used for the treatment of snakebites in this region. No international or regional reference standard for mamushi antivenoms established and authorized by international organizations was available to date. ) Materials and Methods ,Standard mamushi antivenom used for the assay Japanese national standard mamushi antivenom Lot C-48 (established at NIID in 1994) anti-lethal titer: 2,100 U/vial, anti-hemorrhagic titer: 3,300 U/vial, ) (Freeze-dried products) ,Candidate mamushi antivenom Produced by SIBP under the same production protocol for Chinese commercial antivenom products. (Freeze-dried products for long-term storage) Potency tests Determination of anti-lethal titer mouse strains : Slc:ddY at NIID and KAKETSUKEN ICR at KFDA, Kunmin at SIBP ^ > 3 mice/group, body weight 16 20 g Determination of anti-hemorrhagic titer two rabbits (Japanese white strain), body weight approximately 3.0 kg Final results of anti-lethal titer facility test potency 95% confidence interval 1 30,594 Japan 2 31,999 NIID 3 31,328 common potency 31,437 29,111 - 33,949 1 36,310 Japan 2 29,036 Kaketsuken 3 27,342 common potency 31,572 27,066 - 36,827 1 31,256 Korea 2 46,114 KFDA 3 37,638 common potency 36,391 32,832 - 40,335 general common potency 32,909 31,080 - 34,846 (U/vial) Final results of anti-hemorrhagic titer facility test potency 95% C.I. 1 37,847 Japan 2 33,033 NIID 3 29,561 common potency 34,454 33,112 - 35,850 Japan Kaketsuken 37,543 1 42,607 Korea 2 35,402 KFDA 3 42,607 common potency 36,063 34,411 - 37,793 general common potency 36,226 35,440 ዄ- 37,030ዅ U/vial Results of stability test sto?red at stored for (months) ( ) 3 6 9 common 20 0.825 0.830 0.929 0.870 ( 0.635 - 1.011 ) ( 0.974 - 0.974 ) ( 0.799 - 1.078 ) ( 0.792 - 0.954 ) 37 0.710 0.860 0.831 0.818 Potency1 ( 0.544 - 0.866 ) ( 0.743 - 0.997 ) ( 0.715 - 0.964 ) ( 0.747 - 0.964 ) ( 95% C.I. ) 45 0.872 0.837 0.831 0.840 ( 0.663 - 1.098 ) ( 0.717 - 0.971 ) ( 0.715 - 0.964 ) ( 0.766 - 0.921 ) common 0.796 0.843 0.862 0.842 ( 0.703 - 0.902 ) ( 0.775 - 0.916 ) ( 0.794 - 0.936 ) ( 0.799 - 0.888 ) 20 10.716 14.246 12.834 12.281 Regression 2 37 11.003 17.363 12.722 12.090 coefficient 45 8.959 16.411 12.722 11.681 common 10.213 15.954 12.760 12.386 1 ? Anti-lethal titers relative to the candidate stored at 4 for the same period. 2 Regression coefficient of potency. Recommendations summarized in the WHO workshop on the standardization and control of antivenom meeting held in 2001 Even now still remain • Alternative methods to animal test • Viral validation study • Refine test methods Mice test (Lethal) or Rabbit skin test (Hemorrhagic) Conclusion A regional reference standard for mamushi antivenom was successfully established in cooperation with Korea, China, and Japan. The reference standard can be used for quality control of mamushi antivenom products by the currently employed protocols in each country after approval by each NRA. Participated Institutions & Contributors Korea Korea Food and Drug Administration (KFDA) SH Hong, HJ Oh, SJ Hur, KH Lee People’s Republic of China Shanghai Institute of Biological Products (SIBP) Z Wei National Institute for the Control of Pharmaceutical & Biological Products L Dianliang (NICPBP) Japan Chemo-Sero-Therapeutic Research Institute (KAKETSUKEN) K Morokuma, K Ohkuma National Institute of Infectious Diseases (NIID) T Fukuda, M Iwaki, Y Nagaoka, M Takahashi.
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