Knowing the problem of vaccines being frozen because of too cold ice-packs. What about freezers that does not get colder that minus 5'C
Reading the comments, ideas, warnings in this debate about passive cooling over the last several years I get a stronger and stronger feeling that we are chasing the wrong solution for the future. Ice was, at the outset of the coldchain a simple low cost solution demanding compliance but little money.
But experience has shown us that the problems of compliance, accidental freezing, lack of control over temperatures during outreach persist and solutions seem more complex than ever. My hunch is that active cooling solutions that do not requirement removable icepacks will eventually offer a more reliable standard of temperature control, easier and more steamliined standard operating procedures - yes - at a higher cost most likely.
We should be debating the exact requirements of outreach and campaign immunization as we reach out to more remote populations so that equipment designers can be more confident that they are working towards the right performance objectives. We should be asking to evaluate active cooling devices, carried by hand, by 2-whelel and 4-wheel transport. Such solutions should mesh eventually with active cooling generally in the transport sectors of the supply chain.
We may find that the futre coldchain is no longer dependent on ice!
I presume all of you have seen this news item:
The Isobar is specifically designed to maintain stable temperature control between 2C (35F) and 8C (46.4F) during the “final mile” distribution of vaccine in remote regions without power. The cooling effect lasts for up to six days inside an insulated backpack, and can be recharged in just over an hour using either electricity or propane.
I read Umit's comments on freeze protection. I am confident that there is a simple solution to this problem. Umit gave one example, the airliner back back.
Preliminary tests I carried out on my previous entry show that shielding icepacks with a water filled pack can be highly effective. There are probably other simple solutions, what if the carrier was loaded with ice packs the night before a trip if they partially melted be morning they would be conditioned. Even if partially melted they would store more "coolth" than a water pack. If they were still below freezing the freezer temperature could be slightlyincreased to perhaps - 18 deg C.
I noticed an error in my last post. It should have read one .3 liter water pack can shield vaccines from freezing conditions created by four -20 deg C .6 liter ice packs. The original text said two .6 liter packs.
After reading James post indicating the long delay in implementing a safe vaccine carrier I realized a water
barrier to prevent freezing of vaccines could be implemented with currently available ice packs.
For example if the ice packs are at - 20 deg C one water filled .3 liter would be an adaquate barrier for
two .6 liter backs at -20 deg C. The 3 packs could be put together to form a sandwish. they could be
held together by elastic bands.Tubes placed in the holes of the ice packs would help keep the packs
aligned. Sub coooling in the water barrier would probably have to be elliminiated, we have a simple technique
for accomplishing this. Multiple sandwishes of ice packs could be put in the cooler.
Since the materials and cost for this technique are minimal it is unlikely a manufacturer would make
a large investment in developing this type of simple approach. If there is interest and support
we could test and perfest this technique.
I apologize for writing long in my response now. I felt that I have to spell out the logic behind my thinking and had to explain how risk management principles were applied (and should be applied for future) in finding control measures to prevent freezing.
As defined by the ICH Q9, coming up with appropriate control measures against the identified risks requires sound risk management, which is the “systematic application of quality management policies, procedures, and practices to the tasks of assessing, controlling, communicating and reviewing risk”. In a typical risk management process, risk identification, risk analysis and risk evaluation are the first steps to be taken, generally considered as risk assessment. Next step is to put in control measures that would reduce the risk (if cannot be eliminated), and evaluation of the residual risk to see whether it is acceptable. Naturally, the risk should be reviewed on a continuous basis following theintroduction of such measures.
In this regard, I would like to explain, how I came up with the idea of “cool water packs” in 2001.
In a typical risk identification process, we systematically use information to identify potential sources of harm (hazard) referring to the risk question or problem description. Risk identification addresses the “What might go wrong?” question, including identifying possible consequences. This provides the basis for further steps in thequality risk management process. What we were facing was the vaccines being affected by freezing at all levels and everywhere. Within the risk assessment, we started with asking the following questions (for transport of vaccines):
* What might go wrong?
* What is the likelihood (probability) it will go wrong?
* What are the consequences (severity)?
In summary, we can add the answers to these questions as follows:
* Vaccines may freeze
* High likelihood
* Very severe (loss of potency)§
In order to come up with control measures that will either prevent or detect and in the case of anunwanted event occurring, mitigate the impact, we need to analyse “failure mechanisms” to understand proximal causes as well as the root and contributing causes. In this sense, if we focus on the transport of vaccines, the main problem is the presence of ice in passive coolers (freezing of vaccines in storage facilities requires a different risk assessment). The presence of ice is the root-cause; it is the “evil at the bottom”, setting the motion the whole cause and effect chain – it is a factor considered if removal thereof from the problem-fault sequence prevents the final unwanted event (freezing) from recurring.
At this point, I would like to explain one critical point. Again, from the risk management perspective, passive coolers are introduced to “prevent” vaccines from being exposed to temperatures above the acceptable range, and icepacks are introduced as “control measure”. This is fine, but here comes the “residual risk”, the same icepacks that are introduced as “prevention of heat exposure” now becomes a new source of harm for thefreezing of vaccines.
This is why it is critical to question every single control measure you come up with the following questions (this is called “risk control”):
* What is the appropriate balance among benefits, risks and resources?
* Are new risks introduced as a result of the identified risks being controlled?
Having worked for years in the field, I always faced challenges in conditioning of icepacks. When I was working as the Health Coordinator for Operation Lifeline Sudan (UNICEF OLS), it was almost impossible to manage such an operation with conditioning of icepacks. As you can imagine, Sudan is hot, but early morning temperatures are pretty chilly. When you have to bring say 5 boxes of RCW25 with vaccines loaded, to the airstrip in Lokichokio (Kenya) 7 am in the morning, ready to be loaded to aircrafts, how can you condition over 100 icepacks before 7 am when the ambient temperatures are not in your favour? Anyway, that was the triggering point; I said to myself that we need to remove ice from the transport. Of course, I knew about the thermodynamics and the latent phase issues that the cold water will not behave the same way as the ice. I remember, when I made the initial posting on the idea in TechNet those days, I was lectured by others on the latent phase issues that this would never work. But in doing this (eliminating “the evil” from the transport) we were coming up with a control measure that removes the root-cause for good with the help of stability budget of the vaccine products. When I moved to WHO, that was the perfect moment to put this on trial both with laboratory and country level studies. Of course, we know we would go beyond 8 deg C, but we knew the stability budget of every single product. So, the whole issue was about taking the advantage of stability information to exploit it to the extent that such exposures above 8 deg C remain acceptable. The study was published in PDA Journal of Pharmaceutical Science and Technology, Vol. 63, No. 1, January–February 2009. If you are interested to read the article you can reach it here. Following the submission/acceptance of this article, on 8 December 2008 the PQS project has published new performance specifications and verification protocols for insulated containers. In these documents “cool life” is defined as “the empty container is stabilized at +43 °C and loaded with cool-packs which have been stabilized at +5 °C for a minimum of 24 hours. Cool life is measured from the moment when the container is closed, until the temperature of the warmest point inside the vaccine storage compartment first reaches +20 °C, at a constant ambient temperature of +43 °C.” No standard has been set for the cool life, but the performance data is required to be permanently displayed inside the lid. For further details, you may refer to any of the product specification and verification protocol under PQS E004 category page here.
“Cool water packs” is a control measure that “eliminates” the source of harm, and is an adopted technology by many countries today.
Soren’s suggestion of high-temperature freezers came as a “control measure” to the very same problem identified as “vaccine freezing”. The potential problems this control measure brings are as follows:
* The technology is not reliable to produce ice (I explained the reasons in detail in my previous message)
* Even you manage to produce ice, you will still have a negative temperature pack which would be the “source of harm” for vaccine freezing, therefore you would require conditioning
* We know people do not have enough patience for conditioning, field experience shows that compliance levels with “fully conditioning” is very low.
* It will also require huge amounts of investment to phase out existing freezers and replacing them with this solution
Here I would stop and not continue more. From the risk management perspective, this control measure is a “no go” one.
Because one other important issue with control measures is that since themajority of control measures do not provide complete prevention (unless you eliminate the source of harm like in the example of cool water packs), redundant controls are necessary to minimize risk. Like slices of Swiss cheese, the control measures also have holes in them (high-temperature freezers have a very big hole). The system produces failures when a hole in each slice momentarily aligns, permitting (in JT Reason's words) “a trajectory of accident opportunity”, so that a hazard passes through holes in all of the slices, leading to a failure. JT Reason explains the holes in defences arise for two reasons: active failures and latent conditions. In our example of high-temperature freezers - since it will require staff doing the conditioning - when not complied fully it will be an active failure. The latent condition comes from the dormant feature of residual risks in the measure itself. For details of Swiss cheese model please go here and scroll down to the “Swiss cheese model” definition. In summary, this is why I consider high-temperature freezers as a “no go” solution to prevent freezing.
I am sure you all remember the introduction of AD syringes. What was wrong with single use devices? If used correctly (used and discarded) were they safe? Yes. But the problem was the “compliance”. They were re-used. So, the AD syringe introduction removed the root-cause (here the compliance issue) and introduced a new device to replace it as a solution.
Of course, there are other technologies that are more robust in theprevention of freezing, such as freeze free cold boxes and carriers. The very first example of this was the airliner backpack produced by Coldpack and it was PQS prequalified. It was designed in the shape of abackpack, it was light and despite using fully frozen -25 deg C icepacks, it was proven to be freeze-free. Unfortunately, this product was buried among the all other vaccine carriers and could not flag advantage of its “freeze-free” technology in UN catalogues, and the manufacturer decided to take it off the PQS list since they could not enter the market. Though you will not find anything related to the backpack model today, you still can check about the technology here. If ice would be continued to be used, freeze-free carriers would be future, not the conditioning since it comes with serious residual risks.
Lastly, I would like to touch upon James’s comments on the SHAKE TEST. James says that “shake test is unreliable in practice – we know this already”. I do not know where this conclusion is coming from and how come he knows and we do not know. I do not find such claims correct without thesupport of any data.
We know shake test works. Shake test’s positive predictive value is 100%. If it does not work, someone must rewrite the rules of physics that heavy particle don’t sediment faster than a lighter particle (and I bet then he/she would be a new Nobel laureate in physics). Shake test’s validity has been shown under the phase contrast and scanning electron microscopy and both findings are published (as well 100% correct reading results with health staff first time conducting shake test after a training programme). You can read these articles here and here. You can also see the video of the article here and learn more about the shake test here. Currently, we are working on finalizing a new article with my colleagues in Warsaw, Poland, on the structural damages with aluminum-adjuvanted vaccines affected by freezing, but this time using atomic force microscopy.
Keep in mind that from the risk management perspective, shake test is a control measure for “mitigation” of the harm when vaccines are frozen. It starts a control measure for “detection” of vaccines affected by freezing, and furthermore with this detection, by “preventing” use of such vaccines it “mitigates” the harm. It is an excellent control measure (like 3-in-1 appliances).
However, I must say that, recently this year, we have been informed with a case that a particular pentavalent vaccine despite being known for sure that was frozen did not produce the expected “fail” shake test results (which came to market after the 2010 study). I have retested all the vials that were sent to me from the field with no clear answers. I have asked for retained samples from the manufacturer and did the tests myself, still unclear. Now, we are in the process of analysing this particular vaccine under laboratory conditions to understand what happens at the structural level when actual freezing happens and why conglomerates of aluminium is not formed to trigger fast sedimentation. It will take some months to fully study this. And even we find out at the end that there is something different in the formulary that prevents theformation of conglomerates and therefore faster sedimentation, this finding will not discredit the shake test at all. We will issue an exception note that although it is adsorbed, shake test is not applicable to X vaccine from X manufacturer. In this case, we will advise that this particular vaccine from this particular manufacturer must be discarded if exposure to freezing temperature is discovered and/or suspected.
I strongly suggest this video from Blues Brothers when you are conducting a shake test. Believe you me, it helps…
All the best,
James, I also like it.
And I also agree that we should try fix it as simple as possible.
I found in as early as 1998 that vaccines were frozen in ILRs. I did a freeze study in India, which is 18 years ago.
I presented my findings at a meeting in Bangkok, it was not very popular, it was at the time where it was thought …the colder the better.
While I agree on the focus on freeze free CB and VC, freeze free ILRs are available. I think that having the -5C freezers would add to the freeze protection, they should be pre-set like the new ILRs. Not user adjustable. I don’t see the need for user training the temperature cannot be adjusted, just like the freeze free ILRs.
Can we do two things at a time, just a thought
I should admit that i missed out the aspect of latent heat absorption by the icepack at -5C. and i agree with Larry. The risk of vaccine freezing is still likely to be there. Moving towards cool ice packs with vaccine having VVM 7 or higher would allow even longer travels and potent vaccines reaching the children.
We can make the issue complicated or we can try and solve the problem: protect the vaccines from freezing. At present ice packs are not often conditioned and the shake test is unreliable in practice. We know this already.
More than 15 years have passed since PATH documented that vaccines are frequently frozen in the supply chain. Freeze-free refrigerators, boxes are carriers are needed urgently.
Can we achieve at least three manufacturers offering WHO pre-qualified freeze-free cold boxes and carriers within, say, the next 15 months? If not, why not? I suggest that we investigate what’s holding up this process and focus on that.
Even when we have freeze-free cold boxes and carriers available for sale, at least another three or four years will pass before they are adopted in a majority of GAVI eligible countries, not to mention all the other countries. But this will still be faster than coming to a specification and SOPs for -5 degree freezers and getting the tens of thousands (hundreds of thousands?) of health workers to adopt the new SOPs consistently and without error.
Can we focus on solutions that risk solving the problem ASAP. Just a thought.
Thanks to all the contributors to my suggestion.
Naturally, I'm in agreement with Larry.
The only way to find out whether it is working or not, is to test it.
I remember that Umit did a study with waterpacks at positive temperatures, I suggest that the same kind of study be made with -5C (or there about, find the optimal temperature) ice-packs.
Existing freezers 230V or SDD can be modified.
Umit sorry I did not undrstand the beginning of your suggestion. I have also suggested raising the temperature of the freezer to reduce the probability of freezing vaccines I was told that this change would be too complicated. This never made sense to me. Estimates I have done show that the propability of freezing an ice pack increases rapidly with lower freezer temperatures. For example, if an ice pack is at -10 deg C it has four times the potential of freezing vaccine when compared to a -5 deg C pack.
There other advantages to raising the temperature of the freezer such as lower energy consumption. Energy consumption is lowered for a number of reasons:
Less heat will leak through the walls
The cooling system is more efficient at higher evaporator temperatures.
Cooling the ice to a lower temperature takes additional energy.
In addition the run time of the compressor will be longer which will lower the life of the cooling system.
When we were designing our RFVB-134a solar powered refrigerator/freezer and our F 1 SDD freezer, our design philosophy was to design the freezer so that it would make the required amount of ice with the evaporator as close to 0 deg C as possible. This would minimize energy use and reduce the time for conditioning. The SDD freezer typically requires little or no conditioning since the freezer does not run at night. Our freezers were designed to keep the ice packs in direct contace with the freezer, this allows the evaporator temperature to be increased without loosing cooling capacity.
One of the obstacles to setting the evaporator higher is sub-cooling; in a smooth walled container ice does not always freeze at 0 deg, the temperature of the water may have to dip to -5 deg C before it starts freezing. We have developed an essentially no cost method of elliminating sub clooling of a standard ice pack.
Good planning could also allow the temperature to be further increased. Making the required amount of ice in two days rather than one would also allow the temperature of freezer to be increased.
In Kshem's example of an equal number of -5 deg and + 5 deg placed in a carrier. The cold ice packs could freeze the vaccines before equilibrium is reached. To see exactly what is happening in your example you would also have to know the relative heat capacity of ice and the vaccines.
One strategy to keep vaccines from freezing in a carrier is to have a water barrier between the vaccines and ice packs. If the ice packs are colder more water is required an the carrier will be heavier'.
I am currently working as a consultant and would be happy to help with any refrigeration problems presented.
I wish this site had spell check.
Nice post Umit! I agree that we should think through the unintended consequences of making such a seemingly simple change to freezer specifications; here are some other factors to consider:
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Soren’s suggestion for solving one problem creates others.
It takes 10 times the amount of heat energy to be released from a given system of water-based material than it does to absorb heat in that same system. Suggesting that freezers set at - 5° C will, at best, produce an “unreliable” result and is dependent on many inputs: quantity, thermal mass, specific heat, cubic volume, configuration, convection, time, ambient temperature conditions, etc. The rate of heat energy removal required to produce latent heat of crystallization is difficult to attain at -5 ° C, even for very small volumes - which may be good for vaccines but if you are trying to freeze other material such as water packs, forget it. There is simply not enough BTU input to sustain heat removal to the point of crystallization. The greater the volume, the more compounded the problem becomes. There is also the issue of thermostatic control and defrost cycles. If the set-point is –5 ° C it is very likely the temperature triggering the thermostat is –2 or -3 ° C. If it is a frost–free system, the defrost cycle will also be around 0 ° C. This results in a needless waste of energy. Meantime, “nothing freezes”.
By way of suggestion, a more practical approach would be to freeze a material you wish to keep frozen at –18 or –20 ° C and then transfer it to a unit set to –5 ° C, which is not the case for what Soren suggests.
There was an excellent study done by Donnie Wilson at Amgen several years ago to determine the ideal set temperature for freezers with variable capacity loads, taking into consideration the removal of latent heat and specific heat in conjunction with energy consumption and wear-and-tear on mechanicals. Their conclusion? –18 ° C was the sweet spot.
If the concern is freezing of vaccines, using less cold but still at negative temperature icepacks cannot be the solution. We know that conditioning of icepacks does not work; nobody is patient enough to do the full conditioning. This was the main reason; we came up with “cool water pack” concept that is proven to be working in the field. And more importantly, from the risk management perspective, this control measure is fully eliminating the risk of freezing simply by removing ice. Using less cold but at negative temperature icepacks and encouraging staff not to do any conditioning is a very dangerous path. When you drill a hole in the bottom of a leaky boat with the belief you are going to let the water out, it will not help.
(Thanks to Kevin O’Donnell from Biolife Solutions for his inputs to this response)
The ice packs from the freezer at "-5C" would be at -5C, however, the total impact on the load in cold box would be less.
consider in a typical cold box you have loaded sat 10 litres of vaccine at 5 C. The cold box is prepared with another 24 icepacks of 0.4 L at -5 C. This water load = 9.6 L. Mathematically this would reach an equilibrium above 0 C. In addition consider that the temperature of the CB is at ambient - say above +20C.
Of course one would need to be cautious not to put any vaccine in physical contact with the ice packs.
If water pack is frozen in this "-5C" freezer and used in the passive container without conditioning, what would be the initial temperature of those frozen water packs? Will it be still sub-zero?
I fully agree with you Soren. I have suggested this idea to PQS-Secretariat earlier. I am indeed amazed that despite still the high risk of freezing of vaccines during transport, a technological adaptation to freezers has not been considered. a "-5C" freezer would keep the OPV safe and reduce the risk of freezing of liquid vaccines, even if the conditionning was not carried out.