April 15, 2020

Petr Shchedrovitsky: Early and Accurate Diagnostics Play a Critical Role

Petr Shchedrovitsky analyzes the role of early COVID-19 diagnostics in adequate decision-making and the labor division systems involved in the stock test kit production. TechnoSpark runs two point-of-care class test kit projects.

Early and accurate diagnostics play a critical role.

Firstly, it allows the local communities, local administrations and households to make adequate decisions on containing the infection spreading within a given territory. From general considerations, we may suppose that for a large metropolis (e.g. Moscow) it would be perfect to test all its residents within a month, if necessary. In this situation around one million tests would have to be run every day.

Secondly, it may provide an employer with a decision-making tool when it comes to closing the company or, on the contrary, keeping it running. From general consideration it is clear that the more employees there are, the higher is the probability of infection within the staff, provided that the general disease incidence rate is growing. The so-called asymptomatic virus carriers may infect the others and the company will cease its operations.

Today, there is no way of doing it.

Testing remains the bottleneck in the disease incidence rate assessment, taking the appropriate sanitary and epidemiological measures, timely detection and treatment of the infected.

With due regard to the possibility of repeated pandemic waves and the need for the creation of infection-free local zones to ensure normal operation of the economic system, this issue needs to be solved anyway.

Below I will attempt to explain why the solution of this problem turns out to be so challenging almost in all countries of the world. Before dwelling upon a certain situation, let me formulate the general answer as follows.

Just like in any other human activity, here we face the process of development of a complicated “labor division” system.

This LDS includes multiple components, including products or services that still remain the “soft spots” limiting the proper scaling of the system.

Having considered that, let us make a rough analysis of the LDS structure. First of all, there are three test kit (TK) types:

The first is the laboratory test kits that require a standard PCR laboratory (using the polymerase chain reaction method with the result detection). Almost all the official test kits available in Russia fall into this category.

The second type is a point of care TK. Roughly speaking, these are little gadgets that do not require any sophisticated laboratory infrastructure to do the test.

The third type is the anti-body test kits. This is an important element of the general diagnostic system; in the Russian Federation, the first TK of this kind was registered on April 10, but the production wasn’t launched yet.

According to the official data provided by the Government of Russia, on April 13 there were ten (10) TKs, while on March 23 there were four. According to my research, seven of them are designed for PCR laboratories, two are point-of-care-usable and one is for antibody testing. In the nearest future, this number may grow as the new solutions are issued and licensed.

Now let us try to give a detailed analysis of the first TK scaling opportunities. Let me warn you that lots of technical details will be involved, but I count on my readers to keep up with my general logic.

So, if we attempt to make a rough assessment of the LDS in the sphere of laboratory testing, we will see that the immediate commencement of mass testing is not yet possible due to the existing infrastructural limits.

According to the official data provided by the Government, as of April 1, there were 95 laboratories involved in the testing, running 36 thousand tests every day. According to the same sources, by April 13 the number of the laboratories involved reached 254, with 18 of them being private laboratories. It allowed increasing the number of tests to 80-90 thousand per day. Dividing these numbers by the number of laboratories, we will find that each of them runs 350-400 tests per day. In its turn, this laboratory capacity depends on the performance of the central “machine”, the so-called thermocycler or the PCR unit. One thermocycler is capable of running 96 tests at the same time. One full test cycle takes from four to six hours depending on the quality of the labor division system employed by the lab. As a rule, one unit does not run more than two cycles (200 tests) a day, but if the lab has several thermocyclers available and an appropriately adjusted labor division system, then 2 x X (number of thermocyclers) cycles can be performed. It should be added that in real life some units available at the laboratories may not be new and intact, and specialists capable of operating them are also scarce.

According to the official data, there are 410 governmental and private laboratories capable of running the tests in Russia. It means that given this infrastructure and general labor productivity, the number of 150 thousand tests per day can be reached. With a sudden increase of laboratory labor productivity, I believe, the maximum is 250 thousand per day.
At the same time we supposed that in Moscow alone for a proper “disease wave control” it would be preferable to run around one million tests per day. For regions with a population of 1/3 million people, it would be desirable to have the capacity of testing the entire population in one-two weeks.

Doubtlessly, the laboratories need more test kits and a higher test speed (also achieved by changing the chemical composition (ferments)). This is what many developers are striving to achieve. For example, according to the evaluations, the new MBS system developed in Novosibirsk speeds up the PCR analysis procedure by 3-4 times. If it is true, this is a brilliant result. However, as we have already mentioned,

The PCR process is technologically just one of five or six components of the real LDS.

Let us roughly describe this LDS as it is.

The first component is taking a biomaterial sample from the patient. The second component is the delivery of the sample to the lab. The third component is RNA extraction. At the present moment, I believe, this stage takes around 1.5-2 hours. The fourth component is pipetting the samples. If done by a robot, the process takes around 20 minutes, but manually it takes up to one hour. The fifth component is the reverse transcription (out of the virus RNA, a testable DNA is made). It takes 30 more minutes. And only the sixth component is the PCR analysis mentioned above, done with the thermocycler. If I am wrong with any timing data, let specialists correct me. I am not an expert in medical diagnostics, but I am an LDS evaluation specialist.

So, the in-house laboratory process takes around 4-6 hours. Therefore, increasing the PCR analysis speed by three times results in saving as much as one hour. At the current stage of LDS development (to avoid confusion, labor division system) and for an average laboratory, one hour is only 15% of the diagnostic cycle duration. Let’s imagine that we have made an all-out effort and managed to fit not two, but three complete PCR cycles into a common 8-10-hour working day. Let’s imagine that all laboratories of the country have miraculously found the missing qualified specialists and switched to 24-hour work… but as one of the classics said, “He who stands on tiptoe doesn’t stand firm”. The situation is changing for the better, but not dramatically.

But there is more to it.

These days we hear a lot of the so-called false-negative results of the laboratory tests. Let’s figure it out. Firstly, the virus genome is very short; secondly, the virus genome is an RNA molecule, not DNA like that of a human.  The RNA molecule is less stable and decays easily, i.e. it “goes off” on the way to the laboratory. This is why all handling and transportation processes require a strict temperature control. It is generally clear that this rule is often broken for both subjective and objective reasons. This, to my mind, may be the reason for the high incidence of the false-negative results, when the virus cannot be detected even though it is present in the sample. Therefore, this is rather a problem of collection and handling of the samples than quality and accuracy of the tests themselves.

Along with that, there is another component of the LDS in this sphere of activity, which is just as important for understanding its scaling capacity. The matter is the test kit expendables. We often hear people wondering, why there are many different PCR test kits instead of “one proper kit”.

The main thing that needs to be understood is that different test manufacturers have different suppliers, as well as ferment and primer producers.

Some of them are not produced in Russia at all; the production of others is limited. The diversity of the materials produced by different companies or imported from different countries of the world makes the entire structure more stable in general. For Russia the variety of tests is especially important, as many countries (including the US) are currently procuring the test kit expendables at an enormous scale, creating deficit or deficit threat in many other countries.

The main conclusion from the first part of the paper is that we need many developers and producers of test kits. Besides producing the kits on their own, smart developers also issue licenses to the “clear” (contract) manufacturers. This is a way of maximizing investment into this LDS.

If the developers produce everything on their own as they usually do, there will always be a deficiency of tests, as the developers do not have the LDS scaling expertise and therefore will not gain enough investment. The investors will invest only in the company capable of producing various test kits, not to be dependent on one option.

And now let us briefly describe the situation with the second type of test kits (TKs).

The point-of-care units are the devices that combine the stages from 3 to 6 “in one”. A special swab is used to collect the biomaterial from the nose of the patient; the swab is inserted in the device and in 20-40 minutes the result is ready.  Such a unit can be used at airports and companies, i.e. outside the laboratory infrastructure, regardless of the laboratory capacity and size.

For companies with a small number of employees, such point-of-care units can serve as an important element of keeping their operations running during the pandemic.

At the moment, there is only one 100% point-of-care unit approved for COVID tests from sample to result; and it is produced in the US.

In Russia, there are several companies that are working to bring their devices to the market. Some are trying to localize some foreign units, others develop them on their own, but regardless of the business model selected, the task requires a rapid deployment with an adjusted LDS. Let me explain that with a project currently run by TechnoSpark.

One of its startups developed a compact unit capable of processing only one test at a time, but in 15 minutes instead of the standard 40-50. Initially, the device was designed for a different purpose, but the startup developer transformed its latest biosecurity version into a COVID-19 analyzer in two months. Two more months will be spent on starting up the production.

Commenting on this project, the shareholder and CEO of TechnoSpark Denis Kovalevich noticed: “While one of our developer startups is testing and improving the device, another startup is launching the production of the optics with appropriate coating, the third one is providing professional assistance with the registration procedures, the fourth one is at the final stage of designing the device interface, and, even before the official procedures are completed, the fifth one is already negotiating the timeline of supplies for the stock production”. The innovative production labor division system developed by TechnoSpark in the past eight years works as a conveyor for innovations”

Source: Petr Shchedrovitsky


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