POST00391E - PROTECTION OF MORE COLD SENSITIVE VACCINES

Post00391E PROTECTION OF MORE COLD SENSITIVE VACCINES 26 November 2001 ************************* 1. Background 2. Can we return back to the 4-8°C recommended refrigeration range of the 1980s? 3. Can current VVMs be used to prevent freezing? 4. Another priority: to minimize the need for consumable spare parts 5. The lowest 20 cm of ILRs - what to do to prevent freezing? 6. Freezing in the cold boxes: Well-documented problem, but how will the practices change? 7. Eutectics and Glaubers salt 8. Shake test - does it work for DTP-HepB vaccine? 9. International packaging and shipment - Measures to prevent freezing during international transport of vaccines ************************* 1. BACKGROUND In Post00386 (23 October 2001), Bob Davis from UNICEF raised the question of how to protect more cold sensitive vaccines from freezing, and suggested to return to the 4 to 8°C recommended refrigeration range of the 1980s. Furthermore he underlined the importance of low temperature VVM to monitor freezing and asked whether PATH could take on this or whether GAVI could spend window 3 money on this. In the same posting, John Lloyd from PATH, mentioned the efforts to find a "VVM-freeze watch" technology without success to date. John suggested that "eutectic and insulation technologies" and "out of cold chain" seemed to be a solution. He underlined the importance of setting priorities right for the 21st century and suggested the following: Priorities * to avoid freezing vaccines - most 'WHO' equipment places vaccine at the risk of freezing * to minimize energy consumption - so that solar/grid hybrid becomes economic * to maximize portability and robustness - to assure safe distribution and retrieval for repair work on fridges No longer priority * to have a long hold-over time in refrigerators - because vaccines have VVMs and are quite stable * to freeze water icepacks - that put vaccine at risk * to have a long cold life for vaccine carriers - because VVMs permit 'beyond the cold chain' * to promote absorption refrigeration where there is little or no electricity - now that solar/grid hybrid is competitive - and better! John further suggested starting to re-think our priorities for specifying cold chain equipment, both refrigerators and vaccine carriers/cold boxes. In the same posting, Bob Davis came up with another pragmatic suggestion to set the refrigerators at 8°C at noon (or the hottest time of the day) so as not to fall below zero at night, which would not require a policy change. Today's posting is a summary of continued discussion on protection of more cold sensitive vaccines. It summarizes and concludes a total of 48 e-mail exchanges between 1-23 November 2001. Many individuals have participated in this discussion. You will find their contact e-mail addresses in relevant sections. TechNet21 Secretariat ************************* 2. CAN WE RETURN BACK TO THE 4-8°C RECOMMENDED REFRIGERATION RANGE OF THE 1980s? Julie Milstien , Michel Zaffran , Hans Everts , Umit Kartoglu , Philippe Duclos from WHO comment: Below listed points are the reasons why WHO decided to change the recommended storage temperatures -without changing the performance specifications of refrigerators accordingly- from 0-8°C to 2-8°C: * A range from 4-8°C is so narrow that it is extremely difficult if not technically impossible to realize. If at all possible, it would raise the price of refrigerators considerably and cheap models would not stand a chance of survival. Besides, these expensive appliances will be primarily used in central levels and places where there is reliable electricity supply. * It may change the cost of appliances such as ILRs with little guarantee that we will actually achieve the required range. Icelined refrigerators have frozen water in the tubes or icepacks used for the icelining. They suffer therefore from the same limitations: whatever the minimum temperature we recommend, somehow ice made out of H2O does not follow that and stays at 0°C. We can improve the separation between the icelining and the storage compartment, but for the latter to be at +4°C, we do not think there would be much volume left to store vaccine. Eventually, unless fresh 'warm' vaccine is added, the temperatures in the whole appliance will stabilize around the temperature of the icelining. * However, whatever the temperature range we recommend, it is the health worker who sets the thermostat of his appliance and he is not aware of the recommended thermostat setting during the tests. The options are: automatic temperature regulation in the appliance (electronic thermostat); testing on basis of a truly worst case scenario (this would require changing in test procedures). Contrary to what we did some years ago, negative temperatures are no longer accepted in test reports of appliances and all manufacturers have been requested to deal with negative temperatures in their appliances. * It will have no influence on the range of storage temperatures in places where most freezing occurs because these places do not go by what is written in specs but do their best with the environment and energy supply available. * Freezing also occurs during transportation. Icepacks currently melt at freezing point and may spend many hours below freezing if used fresh from the freezer - around 10% of the liquid vaccine in a good cold box will be frozen this way. That does not change unless we put eutectic products in the icepacks, which creates another set of problems. * Avoiding freezing in the periphery may have mean separating refrigerators from freezers- hence another substantial increase in price. As a conclusion three major points can be underlined as priority in addressing preventing vaccine freezing: 1. What can be done easily with the existing equipment to prevent freezing? There are a number of simple (wrapping of freeze sensitive vaccine, icepacks with water, etc.) and not so simple (eutectic products) options. We have to sensitize health workers and storekeepers to the freezing risk, particularly for HepB vaccine, and warn them of risky practices. 2. How can we make sure appliances do not freeze (specifications and test procedures)? The study Soren Spanner did in India in 1997-1998 showed that in ILRs, over a period of two years, the temperature was below –0.5° C more than 50% of the time! 3. How do we move to taking vaccine out of the cold chain, at which levels and what are the repercussions. It may mean that we only need to find solutions for primary and intermediate level storage and can leave the cheaper and smaller peripheral models as they are. ************************* 3. CAN CURRENT VVMs BE USED TO PREVENT FREEZING? Low temperature VVMs continue to be at the centre of the focus whether it is technologically possible, but even it is developed and found its place in the field, it will NOT have any affect on PREVENTION of freezing. It will tell us that "IT'S ALREADY TOO LATE!" James Cheyne from PATH suggests that WHO calls for inventors: "I too am an enthusiast developing, or finding, a better freeze indicator. I know that a search has been going on for some years and nothing has been found yet, but since this approach is not working perhaps we could try something different. How about a public call from WHO for solutions to all indicator manufactures, universities and inventors - similar to what was done to develop AD syringes about 100 years ago? This call for solutions could be backed with funds, as suggested by Bob Davis. Money is a great motivator." Carib Nelson from PATH when commenting on priorities listed by John, touches the exiting VVM as a potential tool to prevent freezing! First of all, Carib suggests to expand the priorities into following: * avoid freezing * create capacity for future vaccines and mono-dose presentations * improve system reliability, performance, and affordability "One approach meeting these criteria that may soon be offered by a US company is a system that works within the current cold chain temperature limits, but eliminates the need for ice. It is a solar-powered, vacuum-panel-insulated refrigerator. Due to the excellent insulation and high efficiency compressor it requires only a single solar panel and no batteries for overnight holdover. It is controlled so that it cannot go below 2°C (at 1°C the panel would power a small heating element). It cannot make ice, but at 4°C it "freezes" ice-pack-like packs filled with a paraffin-based material. These non-ice ice packs fit into a super-insulated outreach carrier which then works just like a normal vaccine carrier with ice -- except the temp won't go below 4°C. The system is more affordable than other solar systems. The company is working on an electric version that would apply the same ice-free principles in a lower cost approach. The company currently supplies the US military and CDC, but is about to submit units for WHO approval. Regarding Bob Davis's call for a freeze monitor. We strongly agree that this would be useful if it could be available in a year or two. PATH continues to comb technologies and talk with potential manufacturers to develop such a product but no suitable technology has yet emerged. We also expect to look into carton monitors or some other improved system monitor that might be more cost-effective and technically feasible within the span of a few years. Paradoxically, VVMs can accomplish a lot in reducing freezing. This tool will allow people to understand that a load of vaccines does not go bad if the power goes out for a night -- they'll be able to see the heat stability of vaccines and begin to accept messages that freezing is a greater danger than mild heat exposure. VVMs will allow out of the cold chain storage, transport and delivery, as is being done in Indonesia with hepatitis-B Uniject -- resulting in a significant savings through 1) vaccine that wasn't frozen, and 2) no additional health center refrigerators needing purchase to accommodate the new vaccine. VVMs are a currently available tool that could play a major role in reducing vaccine freezing." ************************* 4. ANOTHER PRIORITY Since the current GAVI focus issue, John Lloyd from PATH added another priority to the list: " to minimize the need for consumable spare parts". Non-availability of spare parts is the main cause of stoppages of non-electric refrigeration and their procurement and supply line seems so difficult to achieve. Mikko Lainejoki from UNICEF SD commented on the priorities that UNICEF SD warmly supports the suggestions. In parallel he commented that with the recommended priorities we need to tackle operational bottlenecks such as ancient and very rigid performance specifications which do not anymore serve tomorrow's priorities. Mikko sees the need to pursue hybrid systems as one possible solution: "A word of caution about hybrid systems for small scale applications; about 5 months ago we made a quick assessment and contacted five reputable companies and they all had the same view, hybrid systems are competitive alternatives if required output is 2 kW or more. In order to make them cost effective and reliable alternatives in small settings, quite a bit of work remains to be done." Robert Steinglass from BASICS comments on the TechNet21-GAVI cooperation on the issue of vaccine freezing: "One of the conclusions of the recent TechNet meeting in Delhi was that TechNet should be used systematically by GAVI. I think a strong recommendation from TechNet on protection from freezing needs urgently to be brought to the attention of GAVI and all its constituent partners. At the very least, Window 3 (R&D) of GAVI will needs to be accessed." ************************* 5. THE LOWEST 20 cm OF ILRs - WHAT TO DO TO PREVENT FREEZING? John Lloyd , Carib Nelson from PATH; Soren Spanner , Umit Kartoglu from WHO and Robert Davis from UNICEF discuss where to place the freeze sensitive vaccines in ILRs to avoid freezing: It has always been the case that the lowest 20cm or so of the storage area dips below freezing when the ILR is refreezing the ice lining. It is for this reason that the storekeeping training has always emphasized the need to keep TT and DTP and now, HepB in the upper part of ILRs. Carib also commented on how to prevent freezing when using the ILRs even though you place freeze sensitive vaccines at the lowest level of the appliance. "We purchased some VestFrost ILRs for our Lombok Hib study and monitored them carefully. We took the 6" thick blocks of Styrofoam insulation and placed them in the bottom to prevent the possibility of people putting the freeze-sensitive Hib vaccine there. We monitor those refrigerators with a thermometer and a freeze watch at the lowest level of the vaccines. This system has worked well with stable temperatures of 1-2°C." The WHO Product Information Sheets 2000 Edition (WHO/V&B/00.13) page 59 gives a clear explanation and directions how to store freeze sensitive vaccines in ILRs: "Ice-lined refrigerators maintain temperatures below +8°C even with 16 hours electricity failure per 24 hours, day after day. Ice-lined refrigerators are strongly recommended at district, regional and central levels, since electricity supplies are rarely perfect and standby electricity supplies are not practical. An internal lining of water filled tubes or packs that surround the vaccine storage area provides the cooling. In order to freeze this water lining within a limited number of hours when the power is available (8 hours), the compressor has to operate extensively and, occasionally, the vaccine storage area in the bottom of the appliance falls below 0°C. DTP, Tetanus Toxoid and Hepatitis B vaccines should, therefore, NOT be stored within 150 mm of the base of these models. Some models have a mark inside the cabinet, which indicates areas potentially dangerous for the storage of these vaccines." To view the WHO Product Information Sheets 2000 Edition, click on the following link: http://www.who.int/vaccines-documents/DocsPDF00/www518.pdf ************************* 6. FREEZING IN THE COLD BOXES: WELL-DOCUMENTED PROBLEM, BUT HOW PRACTICES WOULD CHANGE? John Lloyd , Carib Nelson from PATH and Umit Kartoglu comment on this well documented problem: In PATH's Indonesia study, it was found that too many and too cold ice packs cause vaccine freezing in cold boxes. Water ice is the best way to store cooling energy - it has the highest latent heat capacity. The problem comes when ice or icepacks are frozen to temperatures well below freezing - such as -20C. If these icepacks are then immediately transferred to insulated boxes the temperature will fall below zero in the icebox for many hours and the vaccines can freeze (about 7-10% have been recorded as being affected in some experiments). John comments: "The [freezing] risk is dependent also on the amount of insulation in the boxes, the long life boxes having the highest risk. Luckily, the risk is hugely reduced for icepacks frozen in the freezing compartment of absorption refrigerators which constitute a majority of the fridges in the field. It was hoped that training people to expose the icepacks to ambient before packing would deal with this risk. I don't think training has had much effect however. Again a design problem that has been faced before... eutectic chemicals raise temperature of freezing but drastically lower cold life. More R& D needed." Conditioning icepacks are the key to prevent freezing due to too cold icepacks. The following extract is taken from a new WHO publication (draft, to be published early 2002) "Guideline for establishing or improving primary and intermediate vaccine stores". This document will replace the old "Guideline for establishing or improving national, regional and district vaccine stores (WHO/EPI/LHIS/96.03)". CONDITIONING ICEPACKS………….."When icepacks are removed from a freezer at (say) - 25°C they need to be kept at room temperature for long enough to allow the temperature of the ice at the core of the icepack to rise to 0°C. This process is called "conditioning". The standard advice has been that an icepack is adequately "conditioned" as soon as beads of water cover its surface. Experiments have shown that this is not always the case and that cold-sensitive vaccines -particularly HepB- can still freeze inside the cold box even when icepacks have apparently been conditioned correctly. When icepacks are laid out on a table they create their own microclimate. This extends the conditioning process. The following procedure is recommended: * Lay out icepacks, preferably in single rows but never in more than two rows. * Leave a 5cm space all round each icepack. * Wait until there is a small amount of liquid water inside the icepacks. This will take up to one hour at +20°C and rather less at higher temperatures. Shake one of the icepacks every few minutes. The ice is conditioned as soon as it begins to move about slightly inside its container." Carl Erickson from Solar Ice Company suggests using a different icemaking system to address freezing problem: "For dealing with vaccine freezing, I would like to suggest the use of an ice-box style refrigerator. Vaccines would be safe because the cooling surfaces cannot go below 0°C. The ice would be supplied by a suitable icemaking system, for example the ISAAC© Solar Icemaker." John Lloyd from PATH questions the suggested appliance: "If Carl's system can freeze at 0°C then there is no problem for vaccines. However, the icepacks will be frozen very slowly and will require refrigeration energy over a long period. The reason for freezing at -20°C is to produce a great temperature difference and therefore and very quick heat flow out of the icepack." ************************* 7. EUTECTICS and GLAUBERS SALT Mogens Munck kindly copied us Ticky Raubenheimer's from Collaborative Centre for Cold Chain Management) message on eutectics. Ticky believes that the use of eutectics must be investigated more: "The session in Delhi also proved that there is some interest in this. Both TechNet and GAVI have agreed that the freezing of vaccines is a very high priority to investigate and find alternative solutions. The use of eutectics can possibly give us an alternative solution - also to make the maintenance of the cold chain more accessible and practical for developing countries. Evaluation of the potency of different vaccines during transportation & storage (including outreach) using eutectics is a sound proposal and can be done quite easily through a laboratory. Our testing chamber (Collaborative Centre for Cold Chain Management) situated at the CSIR in Johannesburg can do the temperature simulations and the South African National Control Laboratory can do the potency testing of the vaccines. Our normal procedures would be; 1. Establish the protocol for testing - all role players and stake holders must identify their needs (the two laboratories can propose the testing protocols); 2. Obtain quotes from the testing centre and control laboratory 3. Get approval of the final contract and funding 4. Collaborative Centre will administer the contract and do the necessary project management 5. Produce a final report." ************************* 8. SHAKE TEST - DOES IT WORK FOR DTP-HEPB VACCINE? Anton Widjaya from PATH suggests a study to see degradation of potency against freezing of vaccines: "Considering that it may take time for us to get data from manufacturers, perhaps it may buy us time if we go ahead and do potency testing (using animals) on frozen routine vaccines. We can freeze samples of different vaccines at different temperatures for various length of time, then test their potency on animals." Umit Kartoglu shares the response WHO received from GSK regarding their product's freezing point and its compliance with shake test. We thank Pascale Binon from GSK for this information, that Titanrix-HB and DTP-HepB vaccine freeze point is MINUS 0.5°C, and the shake test works on both products. SHAKE TEST is designed to determine whether adsorbed vaccines (DPT, DT, Td, TT or hepatitis B) have been frozen. After freezing, the vaccine is no longer a uniform cloudy liquid, but tends to form flakes. Sedimentation occurs faster in a vaccine vial which has been frozen than in a vaccine vial from the same manufacturer which was never frozen. The shake test is most easily demonstrated using a vaccine vial that you personally froze and do not intend to use for immunization. This vial can be used as a "frozen control sample" to be compared with suspect vaccines. If the control vial shows much faster sedimentation than in the vial being tested, the vaccine in question is probably potent and may be used. If, however, the sedimentation rate is similar and contains flakes, the vial under test should not be used. It is important that the shake test is done using both "tested' and "control" vaccine vials produced by the same manufacturer. Test procedure: 1. Take both vials, shake vigorously for 10-15 seconds. 2. Leave vials at rest for 5-10 minutes. 3. View vials against the light ************************* 9. INTERNATIONAL PACKAGING AND SHIPMENT - MEASURES TO PREVENT FREEZING DURING INTERNATIONAL TRANSPORT OF VACCINES Kirsten Myhr from Eastern Health Region Drug Information Centre, Ulleval University Hospital in Oslo, Norway kindly shared with us new services KLM Cargo has introduced for temperature-sensitive pharmaceutical and medical shipments: "The ''Control'' services, which include Control Room, Control Chill and Control Constant, specify the temperature range of various parts of the transport process, such as that in warehouse storage and during air flights, and protection against environmental conditions during loading. In-flight monitoring and flight specific booking for up to five hours before departure is also included. The range has been developed by KLM Cargo Pharmaceuticals Logistics, which is based at Amsterdam's Schipol airport, and the Swedish Envirotainer Group. Envirotainer has developed large containers that can maintain their contents at specific temperatures between -20°C and +20°C, protect them from extreme temperatures, or keep contents at 2-8°C, through the use of battery-powered dry ice systems controlled by thermostats and fans." -----------------------------------------------------------------------------