WORKING PAPER BY DENMARK, FINLAND, ICELAND, NORWAY AND SWEDEN. RESULTS OF A FACILITY DECLARATION TRIAL IN THE FIVE NORDIC COUNTRIES

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1 AD HOC GROUP OF THE STATES PARTIES TO THE CONVENTION ON THE PROHIBITION OF THE DEVELOPMENT, PRODUCTION AND BWC/AD HOC GROUP/WP.173 STOCKPILING OF BACTERIOLOGICAL 18 July 1997 (BIOLOGICAL) AND TOXIN WEAPONS AND ON THEIR DESTRUCTION Original: ENGLISH Seventh session Geneva, 14 July - 1 August 1997 WORKING PAPER BY DENMARK, FINLAND, ICELAND, NORWAY AND SWEDEN. RESULTS OF A FACILITY DECLARATION TRIAL IN THE FIVE NORDIC COUNTRIES During the Ad Hoc Group`s session in March 1997 proposals were put forward on the information to be included in declaration formats (BWC/AD HOC GROUP/WP.139/Rev.1, 20 March 1997). One object of this paper is to further elaborate on these formats and propose some additional information to be included. Another purpose of working out these preliminary declaration formats was to test these on biotechnology industries and other relevant facilities in the five Nordic countries. One aim was also to inform industry of the ongoing negotiations and how a potential declaration system could look including the type of information to be supplied, give industry a possibility to comment on the questions asked and if they see problems with commercial proprietary information. The triggers for declaration used are those discussed in the AHG, but as no final decision on them have been made a set of relevant triggers were tested. The aim being to see if relevant facilities would be triggered and avoiding non-relevant facilities. The following triggers were used: 1.1 Work with listed pathogenic microorganisms, toxins, or components thereof, or work with genetic modification to change pathogenicity or virulence of pathogenic microorganisms (Purely diagnostic work with listed pathogens or toxins are not to be declared) 1.2 Have a production capability in microbiology or biotechnology and also work with listed pathogenic microorganisms, toxins or components thereof 1.3 Production of human and animal vaccines

2 Production of antibiotics by fermentation 1.5 Production of therapeutics by fermentation (excluding vaccines and/or antibiotics) 1.6 Production of other microbial components by fermentation in closed systems 1.7 Have a biosafety level 4 laboratory 1.8 Have a biosafety level 3 laboratory 1.9 Have a production area with containment level category 2 or 3 according to OECD 1.10 Involved in studies of microbial pathogens or toxins in aerosol chambers or in the outdoor environment 1.11 Involved in work with National Biological Defence Programme or related biodefence activities funded by government, defence, or militatry organizations or on behalf of other government In order to simplify the declaration for facilities it is proposed to initially use a screening form (Form 1) where a facility should answer YES or NO for every trigger and if the answer is yes on one or more triggers they are asked to fill in further forms. There is a general information form (Form 2) that all facilities triggered should fill in and in addition a third form for additional information for facilities or part of facilities related to the military that work with microbiology or toxinology (Form 3). Most of the questions asked are constructed so that the replies can easily be computerized. The formats were sent out to a total of 435 facilities in the five Nordic countries during the first half of 1997 and replies were received from 59.1%. The total number of biotechnology companies/facilities is much larger than those triggered using the above mentioned triggers. For the facilities from which replies were received 19.4% (50 out of 257) were triggered to fill in Form 2 and 1.2% to fill in Form 2 and Form 3. Among the facilities giving general facility information 20 were triggered by a single trigger and the rest, 30, by two or more triggers. The most frequent trigger (19,1%) was 1.1 (work with listed pathogenic microorganisms, toxins or components thereof, or work with genetic modification to change pathogenicity or virulence

3 - 3 - of pathogenic microorganisms). Triggers related to production microbiology, 1.2, 1.3 and 1.6 as well as containment triggers,1.8 and 1.9, all have frequencies between 12 and 15% (Table 1).

4 - 4 - Table 1. Trigger frequencies in Form 1 Trigger % Trigger % Trigger % One conclusion from this study is that the number of triggered facilities in the five Nordic countries would be fairly limited. The information given in the formats would give a general picture of the scientific areas and the production capabilities in a country in areas of peaceful uses relevant to the BTWC. Information on sources of finance can complement the general picture of the capabilities in a country. A general conclusion from this trial declaration is that the collected information would increase transparency and build confidence between State Parties. In addition to the formats a separate questionnaire was included where comments and suggestions for the improvement of the content of the formats could be made. One of the questions was if any of the questions in the formats would cause a problem and pose a risk for commercial proprietary information. The only question that caused some concern was to indicate the number e.g. of fermenters. To indicate a facilities fermentation capacity in ranges did not cause any concern. It was also pointed out that the triggers should be easy to understand and well defined. For large companies with several subsidiary companies it was felt that the head office of the company wanted to coordinate answers which should be taken into account when sending out declaration formats in the future. As there was no central register of biotechnology companies in all the five countries there is a risk that the questionnaire was not sent to all relevant facilities but that a few might have been missed. As a consequence of this trial declaration the declaration formats used have been further elaborated and they could be used for further discussion and developement.

5 - 5 - FORM 1, page 1 FACILITY DECLARATION SCREENING FORM Facility Address General description of activities and type of work RESEARCH AND DEVELOPMENT 1.1 Work with listed pathogenic microorganisms, toxins, or components YES NO thereof, or work with genetic modification to change pathogenicity or virulence of pathogenic microorganisms (see ANNEX 1). (Purely diagnostic work with listed pathogens and toxins does not lead to a "YES "answer) If YES fill in FORM 2 [ ] [ ] PRODUCTION MICROBIOLOGY 1.2 Have a production capability in microbiology or biotechnology and also work with listed pathogenic microorganisms, toxins or components thereof (see ANNEX 1) If YES fill in FORM 2 [ ] [ ] 1.3 Production of human or animal vaccines If YES fill in FORM 2 [ ] [ ] 1.4 Production of antibiotics by fermentation If YES fill in FORM 2 [ ] [ ] Production of therapeutics by fermentation (exclusive vaccines or 1.5 antibiotics) If YES fill in FORM 2 [ ] [ ]

6 - 6 - FORM 1, page Production of other microbial components by fermentation in closed YES NO systems If YES fill in FORM 2 [ ] [ ] CONTAINMENT YES NO 1.7 Have a biosafety level 4 laboratory (BL 4, according to WHO Biosafety Manual; see ANNEX 2B) If YES fill in FORM 2 [ ] [ ] 1.8 Have a biosafety level 3 (BL3) laboratory (see ANNEX 2A) If YES fill in FORM 2 [ ] [ ] 1.9 Have a production area with a containment level category 2 or 3 according to OECD recombinant DNA safety considerations, 1986 (briefly defined in ANNEX 3) If YES fill in FORM 2 [ ] [ ] AEROBIOLOGY 1.10 Involved in studies of microbial pathogens or toxins in aerosol chamber or in the outdoor environment If YES fill in FORM 2 and FORM 3 [ ] [ ] MILITARY AND MILTARY- RELATED MICROBlOLOGY AND TOXICOLOGY 1.11 Involved in work with National Biological Defence Programmes or related biodefence activities funded by government, defence or military organizations or on behalf of other governments. If YES fill in FORM 2 and FORM 3 [ ] [ ] Date Signature Return FORM 1 even if all answers are negative

7 - 7 - GENERAL FACILITY INFORMATION FORM 2, page 1 Date 2.1 FACILITY IDENTIFICATION Name(s) of facility Address and geographic location Owner Operator if not owned 2.2 SOURCES OF FINANCE Government % Defence % Private % Other % 23 PERSONNEL Total number (n =) Military (n =) Scientists (n =) Production engineers (n =) Contractor scientists or engineers (n =) Total number working in microbiology or biotechnology (n =) 2.4 FIELDS OF ACTIVITY YES NO Human microbiology [ ] [ ] Animal microbiology [ ] [ ] Plant microbiology [ ] [ ] Environmental microbiology [ ] [ ] Epidemiology or epizootology [ ] [ ] Vaccines [ ] [ ] Pharmaceuticals not vaccins [ ] [ ] Disinfection or decontamination [ ] [ ] Biological insecticides or pesticides [ ] [ ] Aerobiology (in chamber or in outdoor environment) [ ] [ ]

8 - 8 - FORM 2,page TYPES OF ACTIVITY YES NO Diagnostics [ ] [ ] Research and development [ ] [ ] Pilot scale production [ ] [ ] Full scale production [ ] [ ] Multipurpose plant [ ] [ ] Package, storage or distribution [ ] [ ] Field trials in the environment [ ] [ ] 2.6 CONTAINMENT YES NO Do you have laboratories under BL3 or BL4 containment condition (according to the WHO Biosafety Manual: see ANNEX 2 for definitions) [ ] [ ] BL3 laboratories number of units total floor space m 2 BL4 laboratories number of units total floor space m 2 Do you have large scale production units under containment category 2 or 3 (according to OECD Recombinant DNA Safety Considerations, 1986; see ANNEX 3) Number of large scale production units under category 2 Number of large scale production units under category 3 YES [ ] NO [ ] 2.7 BIOREACTOR (FERMENTER) EQUIPMENT YES NO The presence of bioreactors include all fermenters, chemostats, continuous flow fermenters and other vessels, suitable for use for cultivation of microorganisms and cells or production of biological substances including toxins, with a volume of 100 litres or more. [ ] [ ] Total capacity as aggregate volume of vessels, sum of all units in litres: [ ], 1,000-9,999 [ ], 10,000-99,999 [ ], >100,000 [ ] Total capacity as aggregate volume of vessels under containment category 2 or 3 (according to OECD Recombinant DNA Safety Consideration 1986), or containment category BL 3/BL 4 (according to WHO Laboratory Biosafety Manual 2nd ed. 1993), sum of all units in litres:

9 [ ], 1,000-9,999 [ ], 10,000-99,999 [ ], >100,000 [ ]

10 FORM 2, Page SEPARATORS YES NO High speed self sterilizable centrifugal separators or decanters for [ ] [ ] continuous/semicontinuous operation Total aggregate capacity in litres/hour under containment category 2 or 3 (according to OECD Recombinant DNA Safety Consideration 1986) or under BL3 or BL4 containment condition (according to WHO Laboratory Biosafety Manual 2 nd ed. 1993) 2.9 CROSS-FLOW FILTRATION EQUIPMENT YES NO Cross-flow filtration equipment designed for or used for continuous separation of micro-organisms. cell cultures, biological active substances including toxins and having a filter area equal to or greater than 5 square metres [ ] [ ] number of such equipment (n =) 2.10 CELL DISRUPTION EQUIPMENT YES NO Cell disruption equipment capable of continuous operation without the [ ] [ ] release of aerosols and having a flow rate greater than 10 litres/hour 2.11 FREEZE-DRYING EQUIPMENT YES NO Freeze-drying equipment having a condenser capacity greater than 50 [ ] [ ] kg of ice in 24 hours 2.12 WORK WITH GENETIC MODIFICATION OF YES NO MICROORGANISMS Is your company or institute working with genetical modification of [ ] [ ] microorganisms or other infectious elements, or toxins If YES, specify: Microorganisms listed in ANNEX 1 [ ] [ ] Genetic elements from microorganisms listed in ANNEX 1 [ ] [ ] Toxins listed in ANNEX 1 [ ] [ ] Genes which code for toxins listed in ANNEX 1 [ ] [ ] Genetic modifications leading to enhanced or changed virulence or toxicity of any microorganism [ ] [ ]

11 Which microorganisms or toxins listed in ANNEX 1 is your company or institute working with: FORM 2, Page WORK WITH ANIMALS YES NO Do you carry out tests using animals [ ] [ ] Does it involve primates [ ] [ ] Do you develop methods for identification of pathogens or toxins [ ] [ ] Do you carry out work on infectivity or toxicity of human, animal or plant pathogens [ ] [ ] 2.15 AEROBIOLOGY YES NO Do you carry out immunization with aerosols [ ] [ ] Ability to generate aerosols containing particles (droplets) in the respirable range (l-10 µm) [ ] [ ] Indicate total volume of all aerosol chambers for testing or study of biological aerosols or toxins (m 3 ) Total volume of aerosol chambers with BL3 or BL4 standard (m 3 ) Total capacity for liquid aerosols (in ml per minute) Total capacity for powder aerosols ( in gram per minute) 2.16 VACCINE PRODUCTION List the human or animal vaccines you have produced during the last 12 months:

12 FORM 3, page 1 ADDITIONAL INFORMATION FOR FACILITIES OR PART OF FACILITIES RELATED TO THE MILITARY THAT WORK WITH MICROBIOLOGY OR TOXINOLOGY YES NO 3.1 Is the facility or unit part of a National Biological Defence Programme [ ] [ ] For shared facilities, please also provide the following information for the Biological Defence Research and Development portion only: Name of the facility Location (include both address and geographical location) 3.2 Floor area of the laboratory part by containment level BL2 m 2 BL3 m 2 BL4 m 2 Total laboratory floor area (m 2 ) m PERSONNEL Military personnel (n = ) Civilian personnel (n = ) Division of personnel by category Scientists (n =) Engineers (n =) Technicians (n =) Administration and support staff (n =) Are contractor staff working in the facility? If so, provide an approximate number (n = ) 3.4 List the biological disciplines represented in the scientific or engineering staff

13 FORM 3, page What are the sources of funding for the work conducted in the facility where the activity is wholly or partly financed by the Ministry of Defence What are the funding levels for the following program areas (in US $) Research Development Test or evaluation 3.6 Briefly describe the publication policy of the facility 3.7 Briefly describe the Biological Defence work carried out at the facility during the last year, and name the types of microorganisms or other infectious elements, or toxins studied. as well as indoor or outdoor work on biological aerosols 3.8 Provide a list of papers and reports resulting from the work during the previous 12 months, do include authors. titles and full references

14 ANNEX 1 LIST OF PATHOGENS AND TOXINS A. Human pathogenic virus: 1 Crimean-Congo hemorrhagic fever virus 2 Chikungunya virus 3 Eastern equine encephalitis virus 4 Ebola virus 5 Hantavirus 6 Japanese encephalitis virus 7 Junin virus 8 Lassa fever virus 9 Machupo virus 10 Marburg virus 11 Rift Valley fever virus 12 Tick-borne encephalitis virus (Russian spring-summer encephalitis virus) 13 Variola virus (Smallpox virus) 14 Venezuelan equine encephalitis virus 15 Western equine encephalitis virus 16 Yellow fever virus B. Human pathogenic bacteria: 1 Bacillus anthracis 2 Brucella spp. 3 Chlamydia psittaci 4 Clostridium botulinum 5 Francisella tularensis 6 Pseudomonas (Burkholderia) mallei 7 Pseudomonas (Burkholderia) pseudomallei 8 Yersinia pestis C. Human pathogenic rickettsiae: 1 1CoxCoxiella burnetii 2 Rickettsia prowazekii 3 Rickettsia rickettsii

15 D. Human pathogenic fungi: 1. Histoplasma capsulatum (incl. var. duboisii) E. Toxins: 1 Abrin (A. precatorius) 2 Botulinum toxins (Clostridium botulinum) 3 Clostridium perfringens toxins 4 Corynebacterium diphteriae toxin 5 Cyanginosins (Microcystins) (Microcystls aerugmosa) 6 Enterotoxins (Staphylococcus) 7 Neurotoxin (Shigella dysenteria) 8 Ricin (Ricinus communis) 9 Saxitoxin (Gonyaulax catanella) 10 Shigatoxin 11 Tetanus toxin (Clostridium tetani) 12 Tetrodotoxin (Spheroides rufripes) 13 Trichotecene mycotoxins 14 Verrucologen ( Myrothecium verrucaria) F. Animal pathogens: 1 African swine fever virus 2 Avian influenza virus (Fowl plague virus) 3 Bluetongue virus 4 Camel pox virus 5 Classic swine fever virus (Hog cholera virus) 6 Contagious bovine pleuropneumonia /Mycoplasma mycoides var. mycoides 7 Contagious caprine pleuropneumonia/mycoplasma mycoides var. capri 8 Foot and mouth disease virus 9 Herpes B virus (monkey) 10 Newcastle disease virus 11 Peste des petits ruminants virus 12 Porcine enterovirus type 9 13 Rabies virus 14 Rinderpest virus (cattle plague virus) 15 Sheep pox virus 16 Teschen disease virus 17 Vesicular stomatitis virus

16 G. Plant pathogens: 1 Citrus greening disease bacterium 2 Colletotrichum coffeanum var. virulans 3 Chochliobolus miyabeanus 4 Dothistroma pini (Scirrhia pini) 5 Erwiniaamylovora 6 Microcyclus ulei 7 Phytophtora infestans 8 Pseudomonas solanacearum 9 Puccinia erianthi 10 Puccinia graminis 11 Puccinia striiformis (Puccinia glumarum) 12 Pyricularia oryzae 13 Sugar cane Fiji disease virus 14 Tilletia indica 15 Ustilago maydis 16 Xanthomonas albilineans 17 Zanthomonas campestris pv. citri 18 Xanthomonas campestris pv. oryzae

17 ANNEX 2A DESCRIPTION OF THE CONTAINMENT LABORATORY BIOSAFETY LEVEL 3 According to the publication "Laboratory Biosafety Manual, 2nd edition", 1993 from the World Health Organization a Biosafety Level 3 (BL 3) laboratory should include the following features. CODE OF PRACTICE a) The two-person rule should apply, whereby no individual ever works alone in the laboratory b) A biohazard warning sign displayed on laboratory doors must identify the microorganisms handled and the name of the laboratory supervisor who controls access, and indicate any special conditions of entry into the area, e.g. immunization. c) Laboratory clothing that protects street clothing, i.e. solid-front or wrap-around gowns, scrub suits, coveralls, head covering, and where appropriate, shoe covers or dedicated shoes, must be worn in the laboratory. Front-buttoned laboratory coats are unsuitable. Laboratory clothing must not be worn outside the laboratory and it must be decontaminated before it is laundered. d) When appropriate, respiratory equipment must be worn in rooms containing infected animals LABORATORY DESIGN AND FACILITIES 1. The laboratory should be separated from the areas that are open to unrestricted traffic flow within the building. Additional separation may be achieved by placing the laboratory at the blind end of a corridor, or constructing a partition and door or access through an anteroom or Basic Laboratory-Biosafety Level Entry for personnel must be through a vestibule (i.e., double-door entry). 3. Access to the laboratory area must be designed to prevent entrance of arthropods and other vermin. 4. Access doors must be self-closing and lockable. A break-through panel may be provided for emergency use. 5. The surfaces of walls, floors and ceilings should be water-resistant and easy to clean. Openings in these surfaces (e. g. for service pipes) should be sealed to facilitate decontamination of the room(s). 6. The laboratory room must be sealable for decontamination. Airducting systems must be constructed to permit gaseous disinfection. 7. Windows must be closed and sealed. 8. A foot- or elbow-operated hand-wash basin should be provided near to each exit door. 9. There must be a ventilation system that establishes a directional air flow from access spaces into the laboratory room. Staff must verify that proper directional airflow into the laboratory is achieved. 10. In laboratories that have supply air systems, the supply and exhaust facilities must be

18 int erl ock ed to ens ure in wa rd air flo w at all tim es. 11. The building ventilation system must be so constructed that air from the Containment Laboratory-Biosafety Level 3 is not recirculated to other areas within the building. Air may be reconditioned and recirculated within the laboratory. Exhaust air from the laboratory (other than from biological safety cabinets) must be discharged directly to the outside of the building so that it is dispersed away from occupied buildings and air intakes. It is recommended that this air is discharged through high-efficiency particulate (HEPA) filters. 12. Biological safety cabinets should be sited away from walking areas and out of cross cur ren ts fro m do ors, wi nd ow s and ven tila tio n sys te ms.

19 The exhaust air from class I or Class II biological safety cabinets, which will have been passed through HEPA filters, must be discharged directly or through the building system to the outside air. If it is discharged through the building system it must be connected to this system in such a way as to avoid interference with the air balance of the cabinet or the building exhaust system. HEPA filters must be installed in a manner that permits gaseous decontamination and aerosol test challenge. 14. An autoclave for the decontamination of infected waste material should be available in the laboratory room. If such wastes have to be transported to an autoclave in another part of the same building for decontamination, they should be held in a covered, leak-proof container. 15. Anti-backflow devices must be fitted to the water supply. 16. Liquid effluents must be discharged directly to the sanitary sewer. HEALTH AND MEDICAL SURVEILLANCE 17. Medical examination of all laboratory personnel who work in the Containment La bor ato ry- Bio saf ety Le vel 3 is ma nda tor y. Thi s sho uld inc lud e a det aile d me dic al hist

20 A baseline serum sample should be obtained and stored for future reference. 19. Employees who are immunocompromised should not be employed in Containment 20. Special consideration should be given to the employment of pregnant women. ory and a ph ysi cal exa mi nat ion. La bor ato ries - Bio saf ety Le vel 3.

21 ANNEX 2B DESCRIPTION OF THE MAXIMUM CONTAINMENT LABORATORY BIOSAFETY LEVEL 4 The features AF a Containment Laboratory-Biosafety Level 3 (BL 3) apply to a Maximum Containment Laboratory- Biosafety Level 4 (BL 4) with the addition of the following: LABORATORY DESIGN AND FACILITIES 1. Controlled access. Entry and exit of personnel and supplies must be through an airlock or pass-through system. On entering, personnel should put on a complete change of clothing; before leaving, they should shower before putting on their street clothing. 2. Controlled air system. Negative pressure must be maintained in the facility by a mechanical, individual, inwardly directed7 HEPA-filtered supply, and an exhaust air system with HEPA filters in the exhaust and. where necessary, in the intake. 3. Decontamination of effluents. All fluid effluents from the facility, including shower water must be rendered safe before final discharge. 4. Sterilization of waste and materials. A double-door, pass-through autoclave must be available. 5. Primary containment. An efficient primary containment system must be in place, consisting of one or more of the following: (a) Class III biological safety cabinets, (b) positive-pressure ventilated suits. In the latter case a special chemical decontamination shower must be provided for personnel leaving the suit area. 6. Airlock entry ports for specimens and materials. Because of the great complexity of the work, a detailed work manual should be developed and tested in training exercises. In addition, an emergency programme must be devised. In the preparation of this programme, active cooperation with national and local health authorities should be established. Other emergency services, e.g. fire, police, receiving hospitals, should also be involved.

22 ANNEX 3 OECD EXAMPLES OF CONTAINMENT APPROACHES FOR LARGE SCALE INDUSTRIAL APPLICATIONS According to the publication "Safety Considerations for Industrial, Agricultural and Environmental Applications of Organisms Derived by Recombinant DNA Techniques" from the Organisation for Economic Co-operation and Development, 1986, the containment level categories 2 and 3 are partly defined as follows: Specifications Containment categories Closed systems should be located within a controlled area Optional Yes a) Biohazard signs should be posted Yes Yes b) Access should be restricted to nominated personnel only Yes Yes, via an airlock c) Personnel should wear protective clothing Yes A complete change d) Decontamination and washing facilities should be Yes Yes provided for personnel e) Personnel should shower before leaving controlled area Optional Yes f) Effluent from sinks and showers should be collected Optional Yes and inactivated before release g) The controlled area should be adequately ventilated to Optional Yes minimise air contamination h) The controlled area should be maintained at an air Optional Yes pressure negative to atmosphere i) Input air and extract air to the controlled area should be Optional Yes HEPA filtered j) The controlled area should be designed to contain Optional Yes spillage of the entire contents of the closed system k) The controlled area should be sealable to permit fumigation Optional Yes 7. Effluent treatment before final discharge Inactivated by validated chemical or physical means