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mRNA vaccine manufacturing issues and concern.1/ How hard is it to make these things? Isn't it like just putting a drug in an IV bag and you're good to go (like many docs sneered to me to make normal saline from scratch). Well yes, but it depends if you want it to be
2/
1. sterile
2. stable with the same dose, size, etc per vial
3. free of impurities etc
This is why we have regulators like the FDA, HC and the EMA to ensure basic pharmaceutical grade standards. And this also has bearing on safety and efficacy, though that varies re drug&form
1. sterile
2. stable with the same dose, size, etc per vial
3. free of impurities etc
This is why we have regulators like the FDA, HC and the EMA to ensure basic pharmaceutical grade standards. And this also has bearing on safety and efficacy, though that varies re drug&form
3/ Sterility
Sounds easy huh? Not if you want something to be sterile for months or years. For biologicals like vaccines and the mRNA it can be tricky, however, these processes have been all automated standardized. More if interested: https://www.pharm-int.com/aseptic-manufacturing-and-sterile-fill-finish/
Sounds easy huh? Not if you want something to be sterile for months or years. For biologicals like vaccines and the mRNA it can be tricky, however, these processes have been all automated standardized. More if interested: https://www.pharm-int.com/aseptic-manufacturing-and-sterile-fill-finish/
4/ if a vial is multi dose (has more than one dose), then a preservative is added to ensure no microbial growth. For the mRNA vaccines, this is NOT possible as it breaks down the lipids. So all the doses should be drawn up and administered within 6 hrs of the first puncture.
5/ Large vaccination centres in hospitals can do this, though you'd need good technique. Elsewhere, knowing human nature, there will be errors. Lack of labelling, restocking, thawing etc. The risks? Bacterial or more likely fungal contamination.
6/ Stability/Doses. What about these lipid nanoparticles (LNPs)? Making a well-defined mix of solid nanoparticles with consistent mRNA encapsulation, well, hats off to Modern and Pfizer. Thats HARD. They need special machinery and very specialized knowledge.
7/ Some of those LNP themselves have not been approved as separate safe ingredients for use in vaccines, given IM or for use intravenously. Do we know how pure they are, contaminants, toxicity in and of themselves. Pharmacokinetics and dynamics?
8/ We don't have the manufacturing standards to say all the LNPs need to be between 1-3 microns and that at least 90% have mRNA in them. They are likely consistent, but at this early stage there is no guarantee that there are no vials with little or no mRNA....
9/ or that in the process of freezing and thawing that degradation did not occur. Thats why the cold chain is so important. Would prefer pre-filled syringes to improve the stability and sterility issues. I'm sure thats coming.
10/Purity and contamination. This is also a hard step for biological products. How is the mRNA made anyways?
First you need to make the DNA that codes for the RNA. How? Well as I understand it there are commercial vendors that make it synthetically. Then you insert this DNA into
First you need to make the DNA that codes for the RNA. How? Well as I understand it there are commercial vendors that make it synthetically. Then you insert this DNA into
11/ an E coli bacteria by shocking them (lol). The E coli makes the mRNA which you then need to extract using DNAases. It will never be pure mRNA. You'll have some contamination. How much of this E coli DNA is allowed in the vaccines?
12/ There is 10ng on DNA allowed, BUT the potential for genomic integration in combination with these new LNP hasn't been tested. Plus only full length inserts are tested, not fragments, which is more likely since enzymes were used to chew up the DNA to get to the mRNA.
11/ Lets talk about the lipids themselves. The LNPs are not inert like talc in a tablet. They are active pharmaceutical agents in themselves. The regulators agreed with Moderna that only the mRNA would be considered the active agent. But is this appropriate?
12/ Moderna: "The finished product contains two novel excipients, namely SM-102 and PEG2000- DMG. Differences between SM-102 manufacturers are also discussed. It can be concluded that all sites produce comparable quality of SM-102.
13/ Nevertheless, CQAs, CPPs and critical attributes of the materials used for the manufacture of SM-102 are MISSING. The applicant will provide those post-marketing (REC)".
14/ Critical Quality Attributes (CQA)
â A physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality
â A physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality
15/ Critical Process Parameter (CPP)
â A process parameter whose variability has an impact on a CQA and therefore should be monitored or controlled to ensure the process produces the desired quality.
â A process parameter whose variability has an impact on a CQA and therefore should be monitored or controlled to ensure the process produces the desired quality.
16/ So just for 1 of the 4 lipids used in Moderna
A. Has not previously been used IV in humans
B. Has different manufacturer (standardization?)
C. No standard acceptable range for purity, sterility, size of particle etc
D. Wasn't tested for benzene which could be in soluent
A. Has not previously been used IV in humans
B. Has different manufacturer (standardization?)
C. No standard acceptable range for purity, sterility, size of particle etc
D. Wasn't tested for benzene which could be in soluent
17/ For the OTHER novel lipid, PEG-200, "The current reporting of impurities is not acceptable. Characterization data for impurities which are reported under âcontent of unknownâ should be provided post-approval (REC)."
