However, five years later, all the energy exhibited by synthetic DNA companies seems to have evaporated, with some exception. What has happened? Why this lost of interest or this lost of target hitting by those developers/manufacturers of this new technology? It is true that the market environment has not been the most favorable for a sector which is very much dependant on finance rounds, the Russia-Ukranie war and the endless problems in international commerce did not help, but the product is still good. Analytical results are not an opinion and they clearly show that synthetic DNA is free -or almost- of bacterial sequences. The practice demonstrates that huge mounts of synthetic DNA can be obtained in a surprisingly short periods of time, where is then the problem? In my opinion there are a few points that may explain this decay of the synthetic DNA:

1. There are products in the market produced with plasmid, which means that plasmid is good enough for regulators. Against such a business card, you need to do an extraordinary effort to defend a new product and make it attractive enough to make therapy developers assume the risk involved in the novelty.

2. When the product is new, the manufacturer needs to assess the customers on the use of this product closely and patiently, invest time and resources and go side by side with the therapy developer to facilitate the risk mitigation.

3. There is a regulatory front that cannot be ignored, where the simplicity of the synthetic DNA should have a clear advantage versus the plasmid. Have the manufacturers of synthetic DNA profited of this potential?

Finally, there is a niche in my opinion waiting for the synthetic DNA, although is not clear how long it may last. I am talking about the association of synthetic DNA with non-viral vectors, another emerging technology. Both together could make a brilliant solution of the synthetic biology applied to gene therapies, but compromised investors, strong determination and clarity of ideas will be necessary. Do they exist?

Quality means a relevant part of the investment budget. Just the validation of a new manufacturing site takes usually 15% of the construction and equipment acquisition budget, meaning that if we build a 20 million facility to produce biosimilars, as an example, we need to add three more million to get it validated. Neither negligible are the sums that we are going to spend in the validation of the process and analytical methods. The validation of a manufacturing process will take no less than 2 to 4 million to which we have to add the money we will spend in the PPQ runs.

But what I wanted to underline today is how we manage the “hardware” around our process, the number and kind of suites for manufacturing, the quality of components and the level of demand that we are going to impose to our process.

The whole thing has a clear and well identified origin: patient’s safety. This is a red-line that we cannot trespass at all and this is the only real conditionant for the elements making part of our process and facility. In this sense, quality is like a set of russian dolls, so called “matrioskas”. These dolls are all equal to each other but for their size. There is a smallest one which enters in other slightly bigger, this in another one still bigger and so on, until reaching the biggest. Now let’s look to our quality set of measures as if they were russian dolls. The biggest one, the largest matrioska, is the quality that we apply to the manufacturing of a parenteral drug product. This product goes directly to patient’s body and, because of this, any little mistake can be fatal; therefore any precaution is welcome and any expense is assumable. As long as we move to the inside of the matrioska set, we reduce the level of demand of our quality procedures or, better said, we go to less demanding quality standards. Let’s consider this example to illustrate the situation: if we fill vials to inject into a patient, we need a class A surrounded by a class B environment to secure sterility; to make a cell passage during the production we just need a class A in a class C or D, because the biggest disaster that we can produce is the contamination of the next culture stage, which is usually an assumable risk. Did I say risk? Yes, I did. Risk assessment is the key instrument that will allow us to establish the level of demand that we need in the design of our facility.

In recent times I am observing a trend to overreact in terms of quality in facilities dedicated to new therapies. Declare a cell culture process “sterile” is not helping any patient, instead, it is incredibly complicating the operation and making the product more expensive and therefore, of more difficult access to patients. It is in the duties of quality officers and regulators to find the proper compromise between quality and cost, secure patients safety and not making the products harder to obtain by the patients population.