Wednesday, May 5, 2021

Industrial Engineering Suggestions for Productivity Improvement and Cost Reduction of Covid Vaccine Manufacturing - Information Board






 Industrial engineers have to understand current processes used in production systems, alternative engineering methods available in various steps of the process,  visualize ideas or concepts that will give better performance - productivity, analyze the benefit and recommend.

To provide IE suggestions for improving covid vaccine manufacturing process, IEs have to first understand the manufacturing processes of covid vaccines.


Pfizer and Moderna have designed mRNA covid vaccine production systems and are effectively operating them to give vaccines which are working. As industrial engineers it is now our job to do continuous improvement of these effective production systems. I request all industrial engineers to get involved voluntarily and contribute ideas.

In India, Bharat Biotec developed a covid vaccine, covaxin.

In UK, Oxford University and Astra Zeneca developed a vaccine.


Information on Manufacturing Processes of Vaccines

 "How Pfizer Makes Its Covid-19 Vaccine" 

https://www.nytimes.com/interactive/2021/health/pfizer-coronavirus-vaccine.html



It is a complex manufacturing and testing process that takes 60 days.  


STEP 1

Pull DNA from Cold Storage

Vials of DNA from the master cell bank is the source of every batch of Pfizer’s Covid-19 vaccine. The vials are kept at –150°C (–238°F) or below, and they contain small rings of DNA called plasmids.

Plasmid is Coronavirus spike protein gene.

Each plasmid contains a coronavirus gene, the genetic instructions for a human cell to build coronavirus proteins and trigger an immune response to the virus.

The plasmids are thawed. A batch of E. coli bacteria are modified to take the plasmids inside their cells in a vial.

Step 2

Grow the Cells

The vial of modified bacteria (E. coli) is swirled into a flask of amber-colored growth medium, a sterile and warm environment that encourages the bacteria to multiply.

STEP 3

Ferment the Mixture

The bacteria are allowed to grow overnight and then moved into a large fermenter that contains up to 300 liters of a nutrient broth.

The bacterial broth spends four days in the fermenter, multiplying every 20 minutes and making trillions of copies of the DNA plasmids.

STEP 4

Harvest and Purify the DNA

When the fermentation is complete,  chemicals are added to break open the bacteria and release the plasmids from their enclosing cells.

The mixture is then purified to remove the bacteria and leave only the plasmids.

STEP 5

Test for Quality

The plasmids are tested for purity, and compared against previous samples to confirm that the coronavirus gene sequence has not changed.


To know more about plasmids and their use in vaccines, read

Plasmid-Based DNA Vaccines

By Leonardo A. Gómez and Angel A. Oñate

https://www.intechopen.com/books/plasmid/plasmid-based-dna-vaccines

http://www.addgene.org/collections/covid-19-resources/


STEP 6

Cut the Plasmids

After plasmids pass the quality checks, proteins called enzymes are added to the mixture. The enzymes cut the circular plasmids and separate the coronavirus genes into straight segments, a process called linearization that takes about two days.

STEP 7

Filter the DNA Plasmids

Any remaining bacteria or plasmid fragments are filtered out, leaving one-liter bottles of purified DNA. The DNA sequences are tested again.  Each bottle of DNA will produce about 1.5 million doses of the vaccine.

STEP 8

Freeze, Pack and Ship

Each bottle of DNA Plasmids  is frozen, bagged, sealed and packed with a small monitor that will record its temperature in transit.

Up to 48 bottles are packed in a container with enough dry ice to keep them frozen at –20°C (–4°F). 

These containers are sent to facilities where further processing is to be done.  (Andover plant in US and  BioNTech facilities in Mainz, Germany).


STEP 9

Transcribe the DNA Plasmids into mRNA

Five bottles of DNA are thawed for a day, then mixed with the building blocks of messenger RNA. Over several hours, enzymes pry open the DNA templates and transcribe them into strands of mRNA. The finished vaccine will carry the mRNA into human cells, which will read the coronavirus gene and begin producing coronavirus proteins.

The mixture is moved into a holding tank, then filtered to remove any unwanted DNA, enzymes or other impurities. Each batch will  yield up to 7.5 million doses of the vaccine.


About Transcription

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). 

Both DNA and RNA are nucleic acids, which use base pairs of nucleotides as a complementary language. During transcription, a DNA sequence is read by an RNA polymerase, which produces a complementary, antiparallel RNA strand called a primary transcript.

Transcription proceeds in the following general steps:

RNA polymerase, together with one or more general transcription factors, binds to promoter DNA.

RNA polymerase generates a transcription bubble, which separates the two strands of the DNA helix. This is done by breaking the hydrogen bonds between complementary DNA nucleotides.

RNA polymerase adds RNA nucleotides (which are complementary to the nucleotides of one DNA strand).

RNA sugar-phosphate backbone forms with assistance from RNA polymerase to form an RNA strand.

Hydrogen bonds of the RNA–DNA helix break, freeing the newly synthesized RNA strand.

If the cell has a nucleus, the RNA may be further processed. This may include polyadenylation, capping, and splicing.

The RNA may remain in the nucleus or exit to the cytoplasm through the nuclear pore complex.

If the stretch of DNA is transcribed into an RNA molecule that encodes a protein, the RNA is termed messenger RNA (mRNA); the mRNA, in turn, serves as a template for the protein's synthesis through translation. Other stretches of DNA may be transcribed into small non-coding RNAs such as microRNA, transfer RNA (tRNA), small nucleolar RNA (snoRNA), small nuclear RNA (snRNA), or enzymatic RNA molecules called ribozymes as well as larger non-coding RNAs such as ribosomal RNA (rRNA), and long non-coding RNA (lncRNA). Overall, RNA helps synthesize, regulate, and process proteins; it therefore plays a fundamental role in performing functions within a cell.

https://en.wikipedia.org/wiki/Transcription_(biology)

Prokaryotic Transcription

Plasmids 101: The Promoter Region for Transcription

STEP 10

Test the mRNA

Inspection scientists repeatedly test the filtered mRNA to verify its purity and confirm the genetic sequence is correct. 

The output of the batch will be 10 bags of coronavirus mRNA. Each bag holds 16 liters and represents the raw material for about 750,000 doses of the vaccine.


STEP 11

Freeze, Pack and Ship 

The bags of mRNA are frozen to –20°C (–4°F) and shipped to packing facilities (Pfizer facility in Kalamazoo, Mich.,). 

The Andover plant can produce two batches of mRNA a week, each about 10 bags (1.5 million doses). The facility made its first test batch last July, and recently doubled its mRNA capacity by adding a second suite.

STEP 12

Prepare the mRNA

The  the bags of mRNA are kept frozen until needed and then thawed  enough to produce 3.6 million doses of the vaccine, or 600,000 vials.

The thawed mRNA is mixed with water in preparation for making the vaccine.


STEP 13

Prepare the Lipids

In a separate process, the oily lipids that will protect the mRNA and help it enter human cells are produced.  The lipids are measured out and mixed with ethanol. The ethanol  will eventually be removed from the finished vaccine.


STEP 14

Assemble the mRNA Vaccine

A rack of 16 pumps precisely controls the flow of the mRNA and lipid solutions, then mixes them together to create lipid nanoparticles. When the lipids come into contact with the naked strands of mRNA, electric charge pulls them together in a nanosecond. The mRNA is enveloped in several layers of lipids, forming an oily, protective vaccine particle.

Synchronizing eight pairs of pumps is not an ideal solution, but Pfizer engineers chose to scale up existing technology instead of trying to build a larger, unproven type of precision mixing device.

The newly made vaccine is filtered to remove the ethanol, concentrated and filtered again to remove any impurities, and finally sterilized.


Read section Lipid Based Delivery in


Self-assembled mRNA vaccines
Jeonghwan Kima, Yulia Eygerisa, Mohit Gupta, Gaurav Sahay
Advanced Drug Delivery Reviews
Volume 170, March 2021, Pages 83-112

STEP 15

Prepare the Vials

Empty vials are washed and heat sterilized. A set of 13 cameras performs a high-speed visual inspection, taking more than 100 photographs of each vial. Any vials with cracks, chips or other imperfections are removed from the line. A separate machine puts each vial under vacuum to confirm it doesn’t leak.


STEP 16

Rush to Fill the Vials

The flow of vials is narrowed to a single-file line. Machines inject 0.45 ml of a concentrated vaccine solution into each vial, enough for six doses after dilution. The vials are sealed with foil and capped with purple lids, at a pace of up to 575 vials per minute. 

The mRNA will deteriorate if left unfrozen for too long. In 46 hours, the process to get the liquid vaccine into vials has to be completed and then vials are to be put into deep freeze.


STEP 17

Package, Freeze and Test

The filled vials are inspected again, and then labeled and packed into “pizza boxes,” small plastic trays that hold 195 vials each. The trays are bundled in stacks of five and loaded into  industrial freezers. Each freezer holds 300 trays.

It takes a couple of days for the vaccine to reach the –70°C (–94°F) required for long-term storage, and each freezer is tested to ensure that every shelf can maintain that ultracold temperature.

Once frozen, the vials of vaccine are held for four weeks of testing. 

Pfizer currently operates on a 60-day timeline from start to finish, and more than half of that time is dedicated to testing.

STEP 18

Pack and Ship the Finished Vaccine

After  testing, the vaccine is ready to ship. Workers pull trays from the freezers and pack them in shipping boxes with temperature and location sensors. The minimum order is one tray of 195 vials, and a box holds up to five trays. Each box contains 45 pounds of dry ice.  Pfizer is also evaluating different formulations of the vaccine, including freeze-dried and ready-to-use versions that would not require ultracold storage.

Commercial production of the Pfizer vaccine began in September 2020. As of April 22, the plant had delivered more than 150 million vaccine doses to the United States. Pfizer expects to deliver 220 million doses by the end of May, and 300 million by mid-July.


 How Pfizer Makes  Covid-19 Vaccine - More Details on Steps

https://www.nytimes.com/interactive/2021/health/pfizer-coronavirus-vaccine.html



It is a complex manufacturing and testing process that takes 60 days.  


STEP 1

Pull DNA from Cold Storage

Vials of DNA from the master cell bank is the source of every batch of Pfizer’s Covid-19 vaccine. The vials are kept at –150°C (–238°F) or below, and they contain small rings of DNA called plasmids.

Plasmid is Coronavirus spike protein gene.

Each plasmid contains a coronavirus gene, the genetic instructions for a human cell to build coronavirus proteins and trigger an immune response to the virus.

The plasmids are thawed. A batch of E. coli bacteria are modified to take the plasmids inside their cells in a vial.


How to Store DNA


1.Storage in vitreous state

2. Medium length storage

3. Repeatedly freezing and thawing DNA - studies show that repeated freeze and thaw cycles with up to 19 cycles have no detected DNA degradation.

https://www.news-medical.net/life-sciences/How-to-Store-DNA.aspx


Evaluation of DNA Plasmid Storage Conditions 

Manabu Murakami* 

Department of Pharmacology, Hirosaki University, Graduate School of Medicine, Aomori, Japan

The Open Biotechnology Journal, 2013, 7, 10-14

https://benthamopen.com/DOWNLOAD-PDF/TOBIOTJ-7-10/



You have just received your plasmids from Addgene. Now what?

https://www.addgene.org/recipient-instructions/myplasmid/


Plasmid DNA Purification - Macherey-Nagel

https://www.takarabio.com/documents/User%20Manual/PT4022/PT4022-1.pdf

Step 2

Grow the Cells

The vial of modified bacteria (E. coli) is swirled into a flask of amber-colored growth medium, a sterile and warm environment that encourages the bacteria to multiply.

STEP 3

Ferment the Mixture

The bacteria are allowed to grow overnight and then moved into a large fermenter that contains up to 300 liters of a nutrient broth.

The bacterial broth spends four days in the fermenter, multiplying every 20 minutes and making trillions of copies of the DNA plasmids.

STEP 4

Harvest and Purify the DNA

When the fermentation is complete,  chemicals are added to break open the bacteria and release the plasmids from their enclosing cells.

The mixture is then purified to remove the bacteria and leave only the plasmids.



Plasmid DNA Purification - Macherey-Nagel

https://www.takarabio.com/documents/User%20Manual/PT4022/PT4022-1.pdf

STEP 5

Test for Quality

The plasmids are tested for purity, and compared against previous samples to confirm that the coronavirus gene sequence has not changed.


To know more about plasmids and their use in vaccines, read

Plasmid-Based DNA Vaccines

By Leonardo A. Gómez and Angel A. Oñate

https://www.intechopen.com/books/plasmid/plasmid-based-dna-vaccines

http://www.addgene.org/collections/covid-19-resources/


STEP 6

Cut the Plasmids

After plasmids pass the quality checks, proteins called enzymes are added to the mixture. The enzymes cut the circular plasmids and separate the coronavirus genes into straight segments, a process called linearization that takes about two days.

STEP 7

Filter the DNA Plasmids

Any remaining bacteria or plasmid fragments are filtered out, leaving one-liter bottles of purified DNA. The DNA sequences are tested again.  Each bottle of DNA will produce about 1.5 million doses of the vaccine.

STEP 8

Freeze, Pack and Ship

Each bottle of DNA Plasmids  is frozen, bagged, sealed and packed with a small monitor that will record its temperature in transit.

Up to 48 bottles are packed in a container with enough dry ice to keep them frozen at –20°C (–4°F). 

These containers are sent to facilities where further processing is to be done.  (Andover plant in US and  BioNTech facilities in Mainz, Germany).


STEP 9

Transcribe the DNA Plasmids into mRNA

Five bottles of DNA are thawed for a day, then mixed with the building blocks of messenger RNA. Over several hours, enzymes pry open the DNA templates and transcribe them into strands of mRNA. The finished vaccine will carry the mRNA into human cells, which will read the coronavirus gene and begin producing coronavirus proteins.

The mixture is moved into a holding tank, then filtered to remove any unwanted DNA, enzymes or other impurities. Each batch will  yield up to 7.5 million doses of the vaccine.


About Transcription

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). 

Both DNA and RNA are nucleic acids, which use base pairs of nucleotides as a complementary language. During transcription, a DNA sequence is read by an RNA polymerase, which produces a complementary, antiparallel RNA strand called a primary transcript.

Transcription proceeds in the following general steps:

RNA polymerase, together with one or more general transcription factors, binds to promoter DNA.

RNA polymerase generates a transcription bubble, which separates the two strands of the DNA helix. This is done by breaking the hydrogen bonds between complementary DNA nucleotides.

RNA polymerase adds RNA nucleotides (which are complementary to the nucleotides of one DNA strand).

RNA sugar-phosphate backbone forms with assistance from RNA polymerase to form an RNA strand.

Hydrogen bonds of the RNA–DNA helix break, freeing the newly synthesized RNA strand.

If the cell has a nucleus, the RNA may be further processed. This may include polyadenylation, capping, and splicing.

The RNA may remain in the nucleus or exit to the cytoplasm through the nuclear pore complex.

If the stretch of DNA is transcribed into an RNA molecule that encodes a protein, the RNA is termed messenger RNA (mRNA); the mRNA, in turn, serves as a template for the protein's synthesis through translation. Other stretches of DNA may be transcribed into small non-coding RNAs such as microRNA, transfer RNA (tRNA), small nucleolar RNA (snoRNA), small nuclear RNA (snRNA), or enzymatic RNA molecules called ribozymes as well as larger non-coding RNAs such as ribosomal RNA (rRNA), and long non-coding RNA (lncRNA). Overall, RNA helps synthesize, regulate, and process proteins; it therefore plays a fundamental role in performing functions within a cell.

https://en.wikipedia.org/wiki/Transcription_(biology)

Prokaryotic Transcription

Plasmids 101: The Promoter Region for Transcription

STEP 10

Test the mRNA

Inspection scientists repeatedly test the filtered mRNA to verify its purity and confirm the genetic sequence is correct. 

The output of the batch will be 10 bags of coronavirus mRNA. Each bag holds 16 liters and represents the raw material for about 750,000 doses of the vaccine.


STEP 11

Freeze, Pack and Ship 

The bags of mRNA are frozen to –20°C (–4°F) and shipped to packing facilities (Pfizer facility in Kalamazoo, Mich.,). 

The Andover plant can produce two batches of mRNA a week, each about 10 bags (1.5 million doses). The facility made its first test batch last July, and recently doubled its mRNA capacity by adding a second suite.

STEP 12

Prepare the mRNA

The  the bags of mRNA are kept frozen until needed and then thawed  enough to produce 3.6 million doses of the vaccine, or 600,000 vials.

The thawed mRNA is mixed with water in preparation for making the vaccine.


STEP 13

Prepare the Lipids

In a separate process, the oily lipids that will protect the mRNA and help it enter human cells are produced.  The lipids are measured out and mixed with ethanol. The ethanol  will eventually be removed from the finished vaccine.


STEP 14

Assemble the mRNA Vaccine

A rack of 16 pumps precisely controls the flow of the mRNA and lipid solutions, then mixes them together to create lipid nanoparticles. When the lipids come into contact with the naked strands of mRNA, electric charge pulls them together in a nanosecond. The mRNA is enveloped in several layers of lipids, forming an oily, protective vaccine particle.

Synchronizing eight pairs of pumps is not an ideal solution, but Pfizer engineers chose to scale up existing technology instead of trying to build a larger, unproven type of precision mixing device.

The newly made vaccine is filtered to remove the ethanol, concentrated and filtered again to remove any impurities, and finally sterilized.


Read section Lipid Based Delivery in


Self-assembled mRNA vaccines
Jeonghwan Kima, Yulia Eygerisa, Mohit Gupta, Gaurav Sahay
Advanced Drug Delivery Reviews
Volume 170, March 2021, Pages 83-112

STEP 15

Prepare the Vials

Empty vials are washed and heat sterilized. A set of 13 cameras performs a high-speed visual inspection, taking more than 100 photographs of each vial. Any vials with cracks, chips or other imperfections are removed from the line. A separate machine puts each vial under vacuum to confirm it doesn’t leak.


STEP 16

Rush to Fill the Vials

The flow of vials is narrowed to a single-file line. Machines inject 0.45 ml of a concentrated vaccine solution into each vial, enough for six doses after dilution. The vials are sealed with foil and capped with purple lids, at a pace of up to 575 vials per minute. 

The mRNA will deteriorate if left unfrozen for too long. In 46 hours, the process to get the liquid vaccine into vials has to be completed and then vials are to be put into deep freeze.


STEP 17

Package, Freeze and Test

The filled vials are inspected again, and then labeled and packed into “pizza boxes,” small plastic trays that hold 195 vials each. The trays are bundled in stacks of five and loaded into  industrial freezers. Each freezer holds 300 trays.

It takes a couple of days for the vaccine to reach the –70°C (–94°F) required for long-term storage, and each freezer is tested to ensure that every shelf can maintain that ultracold temperature.

Once frozen, the vials of vaccine are held for four weeks of testing. 

Pfizer currently operates on a 60-day timeline from start to finish, and more than half of that time is dedicated to testing.

STEP 18

Pack and Ship the Finished Vaccine

After  testing, the vaccine is ready to ship. Workers pull trays from the freezers and pack them in shipping boxes with temperature and location sensors. The minimum order is one tray of 195 vials, and a box holds up to five trays. Each box contains 45 pounds of dry ice.  Pfizer is also evaluating different formulations of the vaccine, including freeze-dried and ready-to-use versions that would not require ultracold storage.

Commercial production of the Pfizer vaccine began in September 2020. As of April 22, the plant had delivered more than 150 million vaccine doses to the United States. Pfizer expects to deliver 220 million doses by the end of May, and 300 million by mid-July.



Book - Vaccine Development and Manufacturing

Emily P. Wen, Ronald Ellis, Narahari S. Pujar

John Wiley & Sons, 06-Oct-2014 - Technology & Engineering - 456 pages

Vaccine Manufacturing and Production is an invaluable reference on how to produce a vaccine - from beginning to end - addressing all classes of vaccines from a processing, production, and regulatory viewpoint. It will provide comprehensive information on the various fields involved in the production of vaccines, from fermentation, purification, formulation, to regulatory filing and facility designs. In recent years, there have been tremendous advances in all aspects of vaccine manufacturing. Improved technology and growth media have been developed for the production of cell culture with high cell density or fermentation. Vaccine Manufacturing and Production will serve as a reference on all aspects of vaccine production by providing an in-depth description of the available technologies for making different types of vaccines and the current thinking in facility designs and supply issues. This book will provide insight to the issues scientists face when producing a vaccine, the steps that are involved, and will serve as a reference tool regarding state-of-the-art vaccine manufacturing technologies and facility set-up.

Highlights include:

Comprehensive coverage of vaccine production : from a process point of view- fermentation to purification to formulation developments; from a production point of view - from facility design to manufacturing; and from a regulatory point of view - requirements from government agencies

Describes the challenges and issues involved in vaccine production and manufacturing of the different classes of vaccines. 

Preview the book

https://books.google.co.in/books/about/Vaccine_Development_and_Manufacturing.html?id=51O_BAAAQBAJ



More articles - 

on Manufacturing Processes of Vaccines



AstraZeneca





Biontech

How are mRNA vaccines manufactured?
A vaccine based on mRNA is faster to manufacture than conventional vaccines, as only the blueprint and not the antigen itself needs to be produced.

Gavi




Moderna


What does mRNA do? mRNA produces instructions to make proteins that may treat or prevent disease
mRNA medicines aren’t small molecules, like traditional pharmaceuticals. And they aren’t traditional biologics (recombinant proteins and monoclonal antibodies) – which were the genesis of the biotech industry. Instead, mRNA medicines are sets of instructions. And these instructions direct cells in the body to make proteins to prevent or fight disease.


Novavax

https://www.nepic.co.uk/blog/memberposts/county-durhams-glaxo-to-help-make-60-million-doses-of-new-covid-vaccine/

Pfizer










According to a November 2020 report by the U.S. Government Accountability Office (GAO) vaccine manufacturing plant personnel described challenges in obtaining reagents and certain chemicals, as well as glass vials, syringes and other hardware. They also cited a shortage of “fill and finish” facilities where vaccine doses are loaded into sterile containers and a dearth of workers with the specialized skills needed to run mRNA production processes. 

Polymerases, a type of enzyme, that convert DNA to mRNA and ingredients used for making lipid nanoparticles are also some of the most critical raw materials for the vaccines which will be in short supply.  Manufacturers need  a rare substance called vaccinia capping enzyme (VCE), which helps keep the mRNA from degrading and gives it a deceptively human appearance to prevent cells’ protein-making machinery from rejecting it. Making 10 pounds of VCE needed to generate 100 million mRNA vaccine doses additionally would overwhelm the limited capacity of bioreactors (containers used to carry out biochemical reactions) and cost $1.4 billion. 






Resources, Production Scales and Time Required for Producing
RNA Vaccines for the Global Pandemic Demand
Vaccines 2021, 9, 3. https://dx.doi.org/10.3390/vaccines9010003


Pfizer Inc.  and BioNTech SE  project that by the end of 2021 it will produce a total of 1.3 billion doses of its BNT162b2 vaccine, which has 30 µg of mRNA per dose. The production of the BNT162b2 vaccine will take place in several facilities in parallel both in the US and in Europe.

 Moderna Inc.announced the production of a total of 125 million doses of its COVID-19 vaccine
candidate in the first quarter of 2021. This vaccine contains 100 µg of mRNA per dose.
By the end of 2021 Moderna expects to produce between 500 million and 1 billion doses
annually. Additionally, Moderna has outsourced the manufacturing of its mRNA-1273
COVID-19 vaccine to Lonza in Basel, Switzerland, whereby four production lines are being
developed to produce 100 million doses per year per production line.

https://fortune.com/2021/01/25/astrazeneca-covid-vaccines-europe-deliveries-south-africa-price/



Developing mRNA-vaccine technologies
RNA Biol. 2012 Nov 1; 9(11): 1319–1330.

mRNA Vaccine Production and Facility Design
JANUARY 21, 2021 • GUEST POST BY WILLIAM G. WHITFORD

How are mRNA vaccines manufactured?
A vaccine based on mRNA is faster to manufacture than conventional vaccines, as only the blueprint and not the antigen itself needs to be produced.

mRNA Vaccine Era—Mechanisms, Drug Platform and
Clinical Prospection
Shuqin Xu,, Kunpeng Yang , Rose Li  and Lu Zhang
Int. J. Mol. Sci. 2020, 21, 6582; doi:10.3390/ijms21186582

What does mRNA do? mRNA produces instructions to make proteins that may treat or prevent disease
mRNA medicines aren’t small molecules, like traditional pharmaceuticals. And they aren’t traditional biologics (recombinant proteins and monoclonal antibodies) – which were the genesis of the biotech industry. Instead, mRNA medicines are sets of instructions. And these instructions direct cells in the body to make proteins to prevent or fight disease.

mRNA and the future of vaccine manufacturing
February 10, 2021 by David Verga

Cost Estimates of Vaccines


20 Feb 2021
BioNTech's first price estimate for the mRNA vaccine was  €54 per dose (mid June 2020).

Subsequently, BioNTech and Pfizer figured out how reduce costs and build up their manufacturing scale, and made new offers  between €15 and €30 depending on the number of doses purchased.

The U.S. signed a deal for €19.50 per dose on July 22. The EU ultimately signed a deal for approximately €15 per dose



Industrial Engineers - Engineers Specializing in Cost Reduction


Industrial engineers have to understand current processes, visualize ideas or concepts that will give better performance - productivity, analyze the benefit and recommend.

Pfizer and Moderna have designed mRNA covid vaccine production systems and are effectively operating them to give vaccines which are working. As industrial engineers it is now our job to do continuous improvement of these effective production systems. I request all industrial engineers to get involved voluntarily and contribute ideas.

Industrial Engineering Network Linkedin Community 100,320 members

Institute of Industrial and Systems Engineers (IISE) Linkedin Community 83425 members

Please give your suggestions as comments.


Industrial Engineering Suggestions and Ideas for Cost Reduction of Covid Vaccine Manufacturing

Industrial engineers have to do productivity engineering. They need to come out with a concept first. It has to be converted into preliminary design, prototype, detailed design, prototype and convert the detailed design into implemented engineering solution.

Productivity engineering - Engineering to improve productivity and reduce cost. It maintain effectiveness per unit of production and increases quantity produced. So the production system delivers more effectiveness to consumers and earns more revenue for the company from comparable resources. More from the same resources consumed.


Factory in a Box Solution to manufacture vaccines



RNA Vaccines - The production process can be standardized

The production process can be standardized. We anticipate that the production process for RNA vaccines may be able to be scaled and standardized; potentially enabling replacement of the sequence encoding the target protein of interest for a new vaccine with minimal changes to the vaccine production process.

GreenLight’s mRNA Manufacturing Process - Cost Reduction Potential

Substantial cost reduction potential: GreenLight’s mRNA is expected to cost only a fraction of the approximate $10,000 per gram sometimes charged for IVT-produced products.


Optimization of an mRNA vaccine assisted with cyclodextrin-polyethyleneimine conjugates

Drug Deliv Transl Res. 2020 Jun;10(3):678-689. doi: 10.1007/s13346-020-00725-4.


Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines

Molecular Therapy - Nucleic Acids
Volume 15, 15 April 2019, Pages 1-11
Pre-clinical and clinical studies have demonstrated that mRNA delivered intramuscularly (IM) with first-generation lipid nanoparticles (LNPs) generates robust immune responses. Despite progress made over the past several years, there remains significant opportunity for improvement, as the most advanced LNPs were designed for intravenous (IV) delivery of siRNA to the liver.


Using Enzymatic DNA technology

Rather than trying to reduce pressure at the bottleneck of plasmid manufacture by building more capacity, using enzymatic DNA technology it may be possible to eradicate the bottleneck entirely.

Plasmid manufacture is the bottleneck of the genetic medicine revolution

Jonny Ohlson

Drug Discov Today. 2020 Nov; 25(11): 1891–1893.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564888/




Plasmid DNA Production: Productivity with Modular Single-Use Minibioreactors


by Barney Zoro and Andrew Frazer
Tuesday, September 19, 2017  



Time Savings: . Our results indicate that major time savings come with vessel set-up and turnaround, as well as in preparation of ancillary equipment such as feed and reagent bottles for bioreactor monitoring (3 days with single use reactor versus 9.5 days). That is because the single-use bioreactors are presterilized, with precalibrated DO sensors and including multiple feed reservoirs, which significantly reduces the time needed for preparation of ancillaries and thus significantly improves throughput.
Real-world operation of a plasmid DNA product development program at Cobra (including screening and fermentation development stages) using the single-use bioreactor provided a 70% reduction in project timelines — from 46 weeks down to 14 weeks — compared with the same process based on a combination of shake flasks and autoclavable benchtop bioreactors. The increased productivity came from higher culture throughput and improved confidence in data quality.

Those time savings allow for a significant acceleration in clients’ clinical development programs. It speeds programs to initial clinical studies and helps during later stage development when the time available to perform process development activities is restricted by the potential of complicating clinical development programs.

https://bioprocessintl.com/upstream-processing/upstream-single-use-technologies/single-use-minibioreactors-process-development-of-microbial-plasmid-dna/



A Framework to Optimize Production 
Planning in the Vaccine Industry

New Technology for producing Ribonucleoside Triphosphates


Massachusetts-based Snapdragon Chemistry received almost $700,000 from HHS’ Biomedical Advanced Research and Development Authority to develop a new way of producing ribonucleoside triphosphates, a key raw material for mRNA vaccines. Snapdragon’s technology uses a continuous production line, rather than the traditional process of making batches in big vats, so it’s easier to scale up by simply keeping production running for a longer time.

















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