{"operation":"document","citation":"17-0076","title":"Vyriad — Hazardous Materials Safety Interpretation","source_type":"guidance","agency":"Pipeline and Hazardous Materials Safety Administration","status":"guidance","official":true,"published_on":"2018-03-20","effective_on":null,"summary":"17-0076 response to Vyriad concerning 173.134.","machine_formats":{"json":"https://regulus.evalyn.ai/document/phmsa-interpretation-17-0076.json","markdown":"https://regulus.evalyn.ai/document/phmsa-interpretation-17-0076.md"},"app_url":"https://regulus.evalyn.ai/document/phmsa-interpretation-17-0076","source_url":"https://www.phmsa.dot.gov/sites/phmsa.dot.gov/files/docs/standards-rulemaking/hazmat/interpretations/57561/170076.pdf","body":"<<<PAGE 1>>>\n\nU.S. Department\nof Transportation\n1200 New Jersey Avenue, SE\nWashington, DC 20590\nMaterials Safety\nPipeline and Hazardous\nMAR 2 O 2018\nAdministration\nMr. Jon Harrington\nDirector of Manufacturing Operations\nVyriad\n221 1st Avenue SW, Suite 102\nRochester, MN 55902\nReference No. 17-0076\nDear Mr. Harrington:\nThis letter is in response to your July 24, 2017, email requesting clarification of the Hazardous\nMaterials Regulations (HMR; 49 CFR Parts 171-180) applicable to infectious substances.\nSpecifically, you currently offer for transportation two live viruses: 1) Vesicular stomatitis virus\n(Indiana), or VSV, as a Category A infectious substance, and 2) Measles, as a Category B\ninfectious substance. You ask if the HMR provide any exceptions for biological products as\ndefined in § 173.134(a)(2), and if so, whether they may be used for live viruses stored for\nmanufacturing purposes.\nThe answer to both of your questions is yes. As prescribed in § 173.134(b)(6), a biological\nproduct, including an experimental or investigational product or component of a product, subject\nto Federal approval, permit, review, or licensing requirements, such as those required by the\nFood and Drug Administration of the U.S. Department of Health and Human Services or the\nU.S. Department of Agriculture Animal and Plant Health Inspection Service (APHIS), is not\nsubject to the requirements of the HMR as a Division 6.2 material.\nSince APHIS granted you a permit to import and transport the VSV, it is not subject to the\nrequirements of the HMR as a Division 6.2 material. However, because the Measles virus is not\ntransportation in commerce. Live viruses stored for manufacturing purposes are also eligible for\nthe exceptions provided by § 173.134 of the HMR\nI hope this information is helpful. Please contact us if we can be of further assistance.\nSincerely,\n/ Hear roster\nT. Glenn Foster\nChief, Regulatory Review and Reinvention Branch\nStandards and Rulemaking Division\n\n<<<PAGE 2>>>\n\nstevens\n8173.134\nDefentions\nDodd, Alice (PHMSA)\n17:0076\nFrom:\nINFOCNTR (PHMSA)\nSent:\nTuesday, July 25, 2017 4:29 PM\nTo:\nHazmat Interps\nSubject:\nAttachments:\nFW: clarification for shipping\n2017-05-04_600390_Permit_Cover_TO.pdf\nHi Alice,\nPlease submit this as a letter of interpretation. Mr. Harrington spoke with Breanna. Please let me know if you have any\nquestions.\nThanks,\nJodi\nFrom: Jon Harrington [mailto:jharrington@vyriad.com]\nSent: Monday, July 24, 2017 4:13 PM\nTo: INFOCNTR (PHMSA) < INFOCNTR.INFOCNTR@dot.gov>\nSubject: clarification for shipping\nRequesting a formal letter of interp.\nDear DOT,\nThis is a repeat message. I wanted to add a read receipt to make sure you received the information.\nI am looking for some clarification for the shipping of two biological products.\nVyriad is conduction clinical trials using two different types of viruses for treating cancer.\n1.\nMeasles: MV-NIS\nMV-NIS is a live, tissue culture adapted measles virus engineered to express the human thyroidal\nsodium iodide symporter (NIS). The virus was constructed by inserting the NIS gene (cDNA)\ninto a\nfull - length infectious molecular clone of an attenuated Edmonston lineage measles virus (MV-\ntag).\nThis virus is not a vaccine. MV-NIS propagates on Vero cells with kinetics equivalent to the\nparental\nstrain of virus. It propagates selectively in human cancer cells that it infects by binding\npreferentially to\nCD46, a membrane protein that is overexpressed in tumor cell lines. The virus is directly\ncytopathic to\ntumor cells leading to the formation of multinucleated syncytia that die by apoptosis. MV-NIS\ninfected\n1\n\n<<<PAGE 3>>>\n\ntumor cells express NIS, a membrane ion channel that actively transports iodide into cells.\nRadioiodine\nuptake by cells expressing NIS provides the basis for in vivo radioiodine imaging that can reveal\nthe\nprofile of MV-NIS gene expression and the location of MV-NIS infected cells during virus spread\nelimination.\n2. VSV(Vesicular stomatitis virus): VSV-IFN B -NIS\nVSV-IFN B-NIS is a live virus engineered to express both the human interferon ß gene and the\nthyroidal\nsodium iodide symporter (NIS). The virus was constructed by inserting the gene for human IFN\ndownstream of M gene and the NIS gene (cDNA) downstream of the gene for the G protein into\na full-\nlength infectious molecular clone of an Indiana strain VSV. This virus is not a vaccine. VSV-IFN\nB-NIS\npropagates on BHK cells with similar kinetics to the parental strain of virus and can be grown to\nhigh\ntiters. It propagates selectively in human cancer cells since many of them cannot mount an\neffective\nantiviral response mediated via the IN pathway. However, IFN production from infected cells\nwill\nserve to protect non-cancer cells from the effects of the virus. As a result, the virus is directly\ncytopathic to tumor cells leading their rapid lysis with amplification of the virus. VSV-IFN B -NIS\ninfected tumor cells also express NIS, a membrane ion channel that actively transports iodide\ninto cells.\nRadioiodine uptake by cells expressing NIS provides the basis for in vivo imaging with 99mTc\npertechnetate or radioiodine I-123 that can reveal the time dependent profile of VSV-IN B -NIS\ngene expression and the location of VSV-IFN B -NIS infected cells during virus spread and\nelimination.\nCurrently we are shipping 2mL dosages to clinical trials sites using Category B requirements for the\nmeasles virus and Category A requirements for the VSV. Vyriad is required to make sure clinical trial\nsites have a permit for receipt of VSV material through Aphis (see attached). Using Category A and B\nshipping containers are a very costly method of shipping for a startup company like ours and would like\nto explore alternatives if possible. Does this material qualify as an exception $173.134? If the material\nqualifies for an exemption, what classification can we use to ship the materials?\nAdditionally, we have measles and VSV materials stored for manufacturing purposes. Can we ship this\nmaterial under the same exemption?\nI appreciate your time and consideration. How long does the evaluation process normally take? I\nwould like to relay the approximate timeline to my CEO.\nKindest Regards,\nJon Harrington\nDirector of Manufacturing Operations\n2\n\n<<<PAGE 4>>>\n\n= VYRIAD\n221 1st Ave SW, Suite 102, Rochester, MN 55902\nO: 507.722.0231 | M: 608.698.5331 | jharrington@vyriad.com | www.vyriad.com\nNotice: E-mails and attachments sent from this address may\nbe confidential. I very rarely make a mistake but would appreciate\nyou letting me know if you get this note as a mistake. After letting me\nknow, please do not print, distribute or copy the material but\npermanently delete the message and attachments. You can achieve\nthis by deleting the message from your deleted or trash folder. Shredding is\neffective but not recommended.\n3\n\n<<<PAGE 5>>>\n\nUSDA\nUnited States\ngriculture\nepartment o\nHealth Inspection\nAnimal and Plant\nVyriad\nJonathan Harrington\nService\n221 Ist Ave. SW, Suite 102\nServices\nVeterinary\nRochester, MN 55902\nImport and Export\nNational Center for\nThursday, May 4, 2017\n4700 River Road\nUnit 2, Mailstop 22,\nDear Jonathan Harrington:\nRiverdale, MD 20737\nCub. 1A07\nour USDA Veterinary Permit 133771 to import and/or transport controlle\naterials, organisms and vectors accompanies this cover letter\n01) 851-330\nX (301) 851-22\norganisms, or vectors accompanies this cover letter.\nYour USDA Veterinary Permit to import and/or transport controlled materials,\nReviet the permlt carton new pratated segund anguago nay have changed to\nPlease note the following:\n• Review the import permit for errors. Should you identify any errors,\n•lease contact our office immediatelv\n•A copy of the permit must accompany every shipment.\nDe Not send the permit back to this office.\nFor frequently asked questions, permit process and updates,\nour office with\nvisit: www.aphis.usda.gov/animal-health/organisms-vectors. Contact\nany questions or concerns by email at:\nov@aphis.usda.gov or telephone at 301-851-3300, option 3.\nSincerely,\nAPHIS\nSafeguarding Animal Health\nAn Equal Opportunity Provider and Employer\nAPHIS is an agency of USDA's Marketing and Regulatory Programs\nFederal Relay Service\n1-800-877-8339\n(Voice/TTY/ASCI/Spanish)\n\n<<<PAGE 6>>>\n\nDr. Troy Bigelow\nOrganisms and Vectors,\nSenior Staff Officer\nNational Import Export\nand Select Agents\nre: application number 17095116\n\n<<<PAGE 7>>>\n\nANIMAL AND PLANT HEALTH INSPECTION SERVICE\nU.S.DEPARTMENT OF AGRICULTURE\nPERMIT NUMBER\nRIVERDALE, MARYLAND 20737\nVETERINARY SERVICES\n133771\nUNITED STATES VETERINARY PERMIT FOR IMPORTATION\nfile:///D:/netpub/wwwroot/Epermits/images/\nResearch\nAND TRANSPORTATION OF CONTROLLED MATERIALS AND\nDATE ISSUED\nORGANISMS AND VECTORS\n05/04/2017\nDATE EXPIRES\n05/04/2018\nNAME AND ADDRESS OF SHIPPERS)\nCC:\nVyriad\nJon Harrington\nService Center, MN (St. Paul, MN)\nVB-LPD (Ames, IA\n221 Ist Avenue SW, Suite 102\nDA (Rockville, MD\nRochester, Minnesota 55902\nUNITED STATES\nJonathan Harrington\nNAME AND ADDRESS OF PERMITTEE INCLUDING ZIP CODE AND TELEPHONE NUMBER\nU.S. PORTS) OF ARRIVAL\nTRANSPORT PERMIT\n221 lst Ave. SW, Suite 102\nVyriad\n362)\n1483\nRochester, Minnesota 55902\n507-289-0944 / 608-698-5331\nTOLD DAT ONE HAH RITUAL!\nMODE OF TRANSPORTATION\nANY\nAS REQUESTED IN YOUR APPLICATION, YOU ARE AUTHORIZED TO IMPORT OR TRANSPORT THE FOLLOWING MATERIALS\nRecombinant oncolytic Vesicular stomatitis virus (Indiana) - Purified, vialled tissue\nculture-derived virus preparations of recombinant VSV-IFND-NIS\nRESTRICTIONS AND PRECAUTIONS FOR TRANSPORTING AND HANDLING MATERIALS AND ALL DERIVATIVES\nTHIS PERMIT IS ISSUED UNDER AUTHORITY CONTAINED IN 9 CFR CHAPTER 1. PARTS 94,95 AND 122. THE AUTHORIZED MATERIALS OR THEIR DERIVATIVES SHALL BE USED ONLY IN\nACCORDANCE WITH THE RESTRICTIONS AND PRECAUTIONS SPECIFIED BELOW (ALTERATIONS OF RESTRICTIONS CAN BE MADE ONLY WHEN AUTHORIZED BY USDA, APHIS, VS).[\n• Adequate safety precautions shall be maintained during shipment and handling to prevent\ndissemination of disease.\noWith the use of this permit I, Jonathan Harrington, Permittee, acknowledge that the\nregulated material (s) will be imported/transported within the United States in accordance\nwith the terms and conditions as are specified in the permit. The Permittee is the legal\nimporter/recipient [as applicablel of regulated article(s) and is responsible for\ncomplying with the permit conditions. The Permittee must be at least 18 years of age and\nhave and maintain an address in the United States that is specified on the permit; or if\nanother legal entity, maintain an address or business office in the United States with a\ndesignated individual for service of process; and serve as the contact for the purpose of\narticle(s). **Note: Import/Permit requirements are subject to change at any time during\ncommunications associated with the import, transit, or transport of the regulated\nthe duration of this permit.\n•***Materials shall be consigned directly to the permittee address specified above.\ncontinued on subsequent page (s).....\nBEAR THE PERM BEST THE PORT OF ENTRY, BILL OF LADING, AIRBILL OR OTHER DOCUMENTS ACCOMPANYING THE SHIPMENT SHALL\nSIGNATURE\nTroy Bigelow\nTITLE\nSenior Staff Veterinarian\nNO. LABELS\nNational Import Export Services\nVS FORM 16-6A (MAR 95)\nReplaces VS Form 16-3A and 16-28 which are obsolete\nPage 1 of 2\n\n<<<PAGE 8>>>\n\nU.S. DEPARTMENT OF AGRICULTURE\nAPHIS / VETERINARY SERVICES, RIVERDALE, MARYLAND 20737.\nATTACH TO U.S. VETERINARY PERMIT - 133771\nRESTRICTIONS AND PRECAUTIONS: (continued from Permit Form VS 16-6)\n•Work shall be limited only to laboratory studies and or human clinical trials. This permit\ndoes NOT authorize direct or indirect exposure of or inoculation into domestic or\ngoats, swine, and horses). This permit DOES authorize direct and indirect exposure of and\nlaboratory livestock (including but not limited to: birds/poultry/eggs, cattle, sheep,\ninoculation into other animal species\nand for human clinical trials. All exposed\nanimals\nbe held only in isolated facilities with insect and rodent control program in effect.\n• Packaging, containers, and all equipment in contact with the imported products shall be\nsterilized or considered a biohazard and must be disposed of accordingly.\n• Pens,\nsterilized or considered a biohazard and be disposed of accordingly.\ncages, bedding, waste, and dead animals in contact with these materials shall be\n• This permit authorizes the transport of this material into your research and development\nlicensed establishment must be approved by the Center for Veterinary Biologics (CVB).\nfacilities. Introduction of this material into the production areas of your USDA, APHIS,\nStorage locations, movements, and use within your licensed premises must be reported to\n• Imported material, clinical trials and animal trials may be subject to regulations\nenforced by the United States Food and Drug Administration (FDA). Importer must contact\nthe Division of Import Operations and Policy at Area Code (301) 796-0356.\n•THIS PERMIT IS VALID ONLY FOR WORK CONDUCTED OR DIRECTED BY YOU OR YOUR DESIGNEE IN YOUR\nMATERIAL (S) MUST BE SHIPPED/CONSIGNED DIRECTLY TO THE ADDRESS OF THE PERMITTEE OR TO THE\nPRESENT U.S. FACILITY OR APPROPRIATELY INSPECTED LABORATORY. THE AUTHORIZED IMPORTED\nADDRESS OF THE ADDITIONAL PERMITTEE(S) AS IDENTIFIED ON THIS PERMIT. (MATERIALS SHALL NOT\nBE MOVED TO ANOTHER U.S. LOCATION, OR DISTRIBUTED WITHIN THE U.S., WITHOUT USDA, APHIS,\nVS, NIES AUTHORIZATION.) ++EXCEPTION++ Material is authorized to be distributed\nto human\nclinical trial sites, animal testing sites, and biorepository, but Jonathan Harrington,\nVyriad, retains responsibility for compliance to the permit. Locations shall be recorded\nand made available to the USDA upon request.\n• This permit only authorizes exposure to animals for trials associated with development of\nanimal trial requirements must be available to the USDA upon request. Animal trials of any\na human product per direction and guidance of the FDA. Documentation from FDA on FDA\nare not authorized. Contact the Center of Veterinary Biologics for information regarding\ntype for development of an animal product, animal related vaccine or\nderivative thereof\ndevelopment of animal vaccines or products.\n• This permit does not exempt the\npermittee from responsibility\nfor compliance with any\nother applicable federal, state, or local\nand regulations.\n•A copy of this permit must be included with the shipping documents.\nPage 2\nof 2","truncated":false,"body_characters":14418}