Moderna's Issues with Particulates

Maybe even bigger than Pfizer but for different reasons, evidence there is no requirement to follow GMP, and a related filter patent that has a disturbing definition

This is a followup to my Particulates in Pfizer substack and refers to concepts in that substack and is here for reference.

Moderna Did its Homework

In the original authorization by the EMA, called the European Public Assessment Report (EPAR) (Moderna EPAR Jan21) the following is found regarding the LNPs and mRNA in the final durg product.

Since the finished product is presented in multi-dose vials, the applicant has analysed the effect of several preservatives on the biophysical parameters RNA encapsulation, polydispersity and particle size. Results showed an increase of particle size and polydispersity index and a decrease in % RNA encapsulation in the presence of these preservatives. The effects were enhanced after freezing. These results justify the development of the vaccine without preservatives..

So Moderna knew Tris was the preferred buffer and that preservatives commonly used in multidose vials (usually benzalkonium chloride) would cause and increase in particle size of the LNPs and polydispersity index. And most importantly, things got worse after freezing as Pfizer found out to their chagrin.

• mRNA-1273 LNP biophysical attributes (particle size, polydispersity, encapsulation) are not impacted by the different freeze-thaw processes (room temperature or 2°C to 8°C) or 5 cycles of freeze-thaw. (Pfizer had problems with one freeze-thaw cycle with their PBS buffer)

• For lots stored at -20°C, a slight decrease in RNA purity and an increase in process-derived impurities and an increase in particle size can be observed over time; (this is the Oswalt effect discussed in the previous substack) all results were within the specification. At higher storage temperatures, RNA degradation is accelerated, as expected. At 2°C - 8°C after 4 weeks a clear reduction of purity (together with increase of product-related impurities and increase of particle size) is measured

FDA Fact Sheet to Providers Vaccinating for COVID-19

In this document which provided direction to vaccinators is the following regarding administration Moderna Drug Administration info

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The Moderna COVID-19 Vaccine is a white to off-white suspension. It may contain white or translucent product-related particulates. Do not administer if vaccine is discolored or contains other particulate matter.

Am I understanding this right? It is OK if it has visible particulates that are white but ANY OTHER PARTICULATES means you do not administer it? This means Moderna still has VISIBLE PARTICLES on occasion despite using a Tris buffer in the clinical trials and a very long head start based on their mRNA influenza vaccine development program.

So particulates, aggregation and agglomeration with LNPs is an ongoing and serious problem. This deserves a more thorough explanation which I hope to address soon.

The Stainless Steel Particle Fiasco and What It Tells Us About the Vaccine Rollout

I think most of us remember the report in Sept 2021 about contamination of Moderna vials in Japan

Moderna Covid vaccine doses to be recalled by Japanese distributor over stainless steel contamination news report

Biotech firm Moderna has said its Japanese distribution partner will recall three lots of its Covid-19 vaccines after a fourth batch of the company’s shots were found to be contaminated with particles of stainless steel. On Wednesday, the Japanese health ministry confirmed that the contaminants found in Moderna shots were particles of stainless steel and were unlikely to pose any health risks. Moderna’s domestic distributor in Japan, Takeda Pharmaceutical Co, reiterated the findings in a statement, noting “stainless steel is routinely used in heart valves, joint replacements and metal sutures and staples. As such, it is not expected that injection of the particles identified in these lots in Japan would result in increased medical risk.”

Despite the lack of perceived health risk, Moderna said that Takeda would be recalling three lots of the vaccine that were suspended from use due to contamination. Last week Japan halted the distribution of some 1.63 million doses of the jab, with the media reporting that the contaminant was apparently metallic. 

Get that? There are visible particles of stainless steel in the vials BUT NO HEALTH RISKS. And not in just an occasional vial. The first contamination was reported Aug 16 in 39 vials all from the same lot of 57,000 vials. The Japanese authorities eventually recalled three vaccine batches, totalling 1.63 million doses, on September 1st, 2021. By then, the vaccines had been distributed to 863 immunisation centres around Japan, with approximately 500,000 people given doses. There were 3 deaths associated with the recalled batches. Vaccine contamination

A Root Cause Analysis was undertaken and this is what they found. Takeda Report

These vials for Moderna were filled and finished by a company called Rovi, in Spain. Takeda distributed them in Japan. When they started a new manufacturing line it was set up incorrectly during change over prior to Lot 1. Then, there was a vial breakage after the filling of Lot 3, so that issue continued for 5 batches. The human error was misjudging the precise 1mm gap between the star-wheel and the stopper.

Seriously. At the vial breakage after filling of Lot 3, the plant mechanic wasn’t available so the line operator called the on call mechanic AT HOME AND FIXED IT OVER THE PHONE. When Lot 4 failed the visual inspection for visible particles , Lot 5 was actually paused. BUT LOT 4 AND SOME OF LOT 5 WERE SHIPPED OUT ALREADY. And Moderna didn’t think Lots 1 to 3 were affected, but of course they were and the recall got bigger.

So yes, human error but Holy Toledo SOPs at that plant in Spain needed work.

Here is what these particles looked like

Some of those pieces were pretty big and with pointy ends (>500um by 250um). If they were taken up in the needle could they cause granulomas in the bicep? Dislodge and go to the lungs? Since they were stainless steel particles they were deemed inert and used in hip replacements so everyone was told no problem. This is getting close to DNA contamination between regular vaccines and those with LNPs. Smooth large ball and joint stainless steel joint vs lots of tiny sharp shards.

So calling the plant mechanic at home to fix the problem but I guess they were NOT ALLOWED TO STOP THE PRODUCTION OF THE VACCINE for any reason? Especially pesky little visible particles? That are large and look metallic?

THIS TELLS US THAT VACCINE PRODUCTION WAS 365/24/7 AND THAT NOTHING SHORT OF A CATASTROPHIC FAILURE WOULD STOP PRODUCTION, EVEN OVERNIGHT, FOR ISSUES LIKE PESKY VISIBLE PARTICLES.

But Moderna had issues with black particles before and this issue was accepted by the FDA at the time of the EUA (see fact sheet above). Maybe that is why Rovi thought they could get away with it? I guess Moderna had other issues with particulates in addition to:

1. amorphous white particles (likely agglomerate LNPs)

2. stainless steel particles

3. other particles

Black Particles in the Moderna’s Bivalent Jabs Sept 2022

At the launch of Moderna’s Bivalent jabs, their contract manufacturer was issued a Form 483 from the FDA. What is a Form 483? see FDA Form 483

An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgment may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts. FDA investigators are trained to ensure that each observation noted on the FDA Form 483 is clear, specific and significant. Observations are made when in the investigator’s judgment, conditions or practices observed would indicate that any food, drug, device or cosmetic has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or rendered injurious to health.

You mean the FDA was doing its job? Or at least some of their analysts? It appears so, at least in 2022. article

Catalent hit with FDA 483 at Bloomington plant

by Millie Nelson Thursday, September 22, 2022  7:23 am

A US FDA Form 483 has revealed visible foreign particles in certain batches of drug product at Catalent’s Bloomington, Indiana facility.

The Bloomington plant, which offers fill and finish services and commercial scale production, was handed a Form 483 from the US Drug and Food Administration (FDA) following an inspection at the facility between August 1 and September 1.

The 483 detailed that the FDA identified 179 occasions where particles, like black specks, foreign matter, particular matter, and foreign objects and pieces were discovered in vials produced by the contract development manufacturing organization (CDMO) .

These included Moderna’s bivalent jabs. Most interesting is this observation by Moderna.

“In the event that [the] FDA ultimately determines that the Catalent facility was not operating in compliance with cGMP requirements at the time these batches were manufactured, Condition I in the Moderna COVID-19 Vaccine Letter of Authorization will be waived as to these batches,” the document said.“In the event that [the] FDA ultimately determines that the Catalent facility was not operating in compliance with cGMP requirements at the time these batches were manufactured, Condition I in the Moderna COVID-19 Vaccine Letter of Authorization will be waived as to these batches,” the document said.

WELL THERE YOU HAVE IT IN BLACK AND WHITE. MODERNA DOES NOT HAVE TO FOLLOW GOOD MANUFACTURING PRACTICES FOR THEIR COVID JABS.

So did these lots get sent out to patients? What do YOU think? Of course, Director Marks overrode the FDA agents findings on the Form 483 AND THE BATCHES WERE RELEASED. It is worthwhile reading the explanation: Mark's Letter

CBER’s Office of Vaccine Research and Review (OVRR) has carefully reviewed this information and determined that all applicable specifications were met for these batches. Thus, OVRR does not have safety, effectiveness, or quality concerns with these batches, and has concluded that they are suitable for use.re the bivalents

If you were an FDA analyst, how would you feel? This is similar to what I saw with the EMA leak.

Was There a Problem With the Filters They Used? Or Is it the LNPs themselves?

On a whim I looked for issues with the filters and I found papers that looked at the filters used by Moderna to filter the final product prior to the fill and finish steps.

What I found is that the overlap in the size distribution between the vaccine and the sterilizing grade membrane (at 0.2um) can result in retention of vaccine particles on or within the sterilizing grade filter which causes

• significant yield loss

• large increase in resistance to filtration

Here is what a buffer looks like on the left, and what the LNPs look like on the right after filtration until they basically cant filter any more. The buffer keeps its overall shape. The LNPs form an amorphous mass. Is that why there are amorphous visible particles? Or the black particles? And then reused these filters?

https://www.sciencedirect.com/science/article/abs/pii/S0376738823005525 and https://onlinelibrary.wiley.com/doi/10.1002/bit.28200

(both behind paywalls, sorry. I got one of them for this picture).

The mRNA-LNPs appear to foul the dual-layer filter by blocking the pores in the downstream sterilizing-grade membrane layer, as demonstrated both by scanning electron microscopy and derivative analysis of filtration data collected for the two layers independently. These results provide important insights into the mechanisms governing the filtration of mRNA-LNP vaccines and therapeutics.

Important insights, huh. No one had a clue what it was going to be like filtering these products at scale. What was interesting is that the LNPs did not act like a compressible deposit OR an incompressible deposit but that the nature of “fouling” is dependent on the pressure (of buffer) applied to the filter. Can that be translated clinically? These are synthetic fats. Yeah I can imagine them forming insoluble amorphous hard to remove blotches.

Comments anyone?

Lastly, a Patent on Filters for LNPs That Has a Disturbing Comment

I also found this patent by Flagship Pioneering Innovations. From what I understand from Kevin McKernan is that Noubar Afeyan, the Founder of Moderna was from Flagship (though he is not on the patent). So it appears this is a patent to use for UF/DF of the mRNA.

But it does talk about purifying LNPs using TFF and these filters. But on Page 6 I find this:

Did you see that?

LNP+mRNA+gRNA is an assembled LNP (gRNA is guide RNA). Guide RNA is a piece of RNA that functions as a guide for RNA- or DNA-targeting enzymes, with which it forms complexes. Very often these enzymes will delete, insert or otherwise alter the targeted RNA or DNA.

So what does a patent filed Jan 2020 by a company founded by the man who founded Moderna talking about LNPs containing guideRNA? Might be nothing and only a coincidence.

What do you think? Comments welcome.

Thanks for reading.