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π Health and biotech
Beyond Covid: the promise of mRNA vaccines

Bioproduction of mRNA vaccines: a global industrial challenge?

Agnès Vernet, Science journalist
On December 8th, 2021 |
4 mins reading time
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Bioproduction of mRNA vaccines: a global industrial challenge?
Emmanuel Dequier
Emmanuel Dequier
Programme Manager for Grand Challenge Bioproduction
Key takeaways
  • RNA molecules have inestimable potential for the medicine of tomorrow. However, its bioproduction requires technical steps that put it at the crossroads between technological issues and industrial policies.
  • For the production of pharmaceutical grade RNA, steps must be certified as Good Manufacturing Practice (GMP). The production of certified template DNA is limited in the United States, so obtaining it involves a time constraint of several months.
  • Today, numerous technical innovations allow us to limit all these production constraints, and a lot of research continues to move in this direction.
  • The global pharmaceutical market is worth over $1,300bn. If we include new biotechnologies, it could reach $4,800bn. This is an unsustainable amount for our health systems, so the issue of finance is central to the future of biotherapies.

RNAs are of inter­est in many med­ical fields. How­ev­er, to ful­ly under­stand their val­ue and bring them to patients we need to be able to pro­duce them. RNA bio­pro­duc­tion is at the cross­roads between tech­no­log­i­cal issues and indus­tri­al policy.

The last few months have shown that we are capa­ble of deliv­er­ing bil­lions of dos­es of mes­sen­ger RNA (mRNA) vac­cines. This might lead us to believe that the pro­duc­tion sys­tems for these bio­log­i­cal mol­e­cules are ready. How­ev­er, in real­i­ty, this is not the case. New man­u­fac­tur­ing capac­i­ties need to be antic­i­pat­ed: more and more clin­i­cal tri­als are eval­u­at­ing RNAs in med­ical appli­ca­tions, for exam­ple in can­cerol­o­gy, as a treat­ment for emerg­ing dis­eases or genet­ic dis­eases. These are mRNAs, as in the case of vac­cines against Covid-19, or oth­er types of RNAs, anti­sense or effec­tors, which block or acti­vate bio­log­i­cal process­es. Ther­a­peu­tic inter­est in these mol­e­cules is grow­ing rapid­ly and pro­duc­tion tools and tech­nolo­gies need to keep pace.

To appre­ci­ate the issues at stake, it is impor­tant to look at pro­duc­tion process. RNAs are syn­the­sised in vit­ro using a DNA tem­plate and an enzyme: RNA poly­merase. The RNA is then puri­fied on chro­matog­ra­phy columns, which take advan­tage of chem­i­cal prop­er­ties (pH or affin­i­ty) to sep­a­rate the com­po­nents of the solu­tion and iso­late the prod­uct of inter­est. Final­ly, the RNA mol­e­cules are asso­ci­at­ed with vec­tors, i.e. envelopes that pro­tect these frag­ile mol­e­cules and facil­i­tate their entry into the cell when the RNA drug is administered.

In short supply

In order to pro­duce phar­ma­ceu­ti­cal grade RNA, all these steps must be cer­ti­fied as Good Man­u­fac­tur­ing Prac­tice (GMP). This stan­dard is based on a large num­ber of con­trols to ensure patient safe­ty, start­ing with the pro­duc­tion of tem­plate DNA. Glob­al­ly, there are very few man­u­fac­tur­ers able to per­form this step in accor­dance with GMP stan­dards and none are locat­ed in Europe. The main pro­duc­ers of GMP DNA tem­plates are in the US and it takes many months to get access to the desired DNA. Glob­al­ly, there is there­fore a high demand for this prod­uct that is in short sup­ply, a sit­u­a­tion which has been exac­er­bat­ed by the covid-19 pan­dem­ic. In response, the Resilience part of the France Relance recov­ery plan* has pro­vid­ed the Besançon-based com­pa­ny RD Biotech with €2 mil­lion in for the con­struc­tion of a new GMP stan­dard DNA pro­duc­tion site of over 1,000 m².

There are also sup­ply issues con­cern­ing access to the enzyme, RNA poly­merase, which reads the DNA tem­plate in order to syn­the­sise RNA. How­ev­er, Enzyme pro­duc­tion is well con­trolled, and the phar­ma­ceu­ti­cal indus­try there­fore tends to inter­nalise it to secure its supply.

Final­ly, these process­es require a large num­ber of con­sum­ables (fil­ter, plas­tic bag, etc.). The major pro­duc­ers of these mate­ri­als are also out­side Europe and there is cur­rent­ly a mar­ket short­age when it comes to these prod­ucts. In response to the health cri­sis, man­u­fac­tur­ers are now organ­is­ing them­selves in order to avoid sup­ply dis­rup­tions in the event of fur­ther bor­der clo­sures. For exam­ple, the Mer­ck com­pa­ny is going to set up a new pro­duc­tion unit for ster­ile bags, nec­es­sary for the pro­duc­tion of vac­cines, in Mol­sheim in Alsace.

Industrial innovations

Indus­tri­al research is prepar­ing new process­es in par­al­lel with these short-term adjust­ments. The plan is to move from in vit­ro pro­duc­tion (enzy­mat­ic syn­the­sis) to in vivo pro­duc­tion, by using yeast to pro­duce the RNA. This strat­e­gy has many advan­tages. First­ly, it avoids the need to pro­duce RNA poly­merase, which is nat­u­ral­ly pro­duced by yeast. Sec­ond­ly, it lim­its the indus­tri­al risks asso­ci­at­ed with the use of very large vol­umes of high­ly explo­sive ethanol dur­ing the pro­duc­tion process. Third­ly, as the cells are equipped with mul­ti­ple sys­tems to improve the accu­ra­cy of the tran­scrip­tion (by low­er­ing the error rate inher­ent in each RNA poly­merase), the RNA pro­duced will be of high­er qual­i­ty. It will also be pos­si­ble to pro­duce longer RNAs and to devel­op increas­ing­ly com­plex appli­ca­tions such as mul­ti­va­lent vac­cines, notably with vac­cines direct­ed against dif­fer­ent flu vari­ants. Final­ly, in vivo pro­duc­tion will allow mod­i­fi­ca­tions to be made to the mol­e­cule after it has been syn­the­sised, still in the yeast cell. These mod­i­fi­ca­tions can, for exam­ple, ‘human­ise’ the bio­mol­e­cule and thus increase its lifes­pan and effec­tive­ness in human cells.

In vivo pro­duc­tion sys­tems such as this one are being devel­oped in France as part of a col­lab­o­ra­tive pro­gramme sup­port­ed for which Grand Défi “Bio­med­i­cines: improv­ing yields and con­trol­ling pro­duc­tion costs” has pro­vid­ed €1.4M of sup­port. This research pro­gramme led by Chan­tal Pichon (Univ. d’Or­léan) at the CNRS Mol­e­c­u­lar Bio­physics Cen­tre, in part­ner­ship with INSERM, INRAe, and the Poly­théragène and Sanofi-Pas­teur com­pa­nies, is expect­ed to reach indus­tri­al matu­ri­ty in three to five years. The French phar­ma­ceu­ti­cal giant has also shown its will­ing­ness to devel­op its RNA pro­duc­tion by acquir­ing the Amer­i­can biotech­nol­o­gy com­pa­ny Trans­late Bio. It plans to set up an RNA pro­duc­tion unit at its Mar­cy-l’É­toile site in the Lyon region.

A sustainable price

Oth­er avenues of research com­bine a med­ical and eco­nom­ic advan­tage. They focus on address­ing ther­a­peu­tic mol­e­cules, i.e. the pre­ci­sion with which RNAs reach the patient’s tar­get cells. By reduc­ing the dis­per­sion of the mol­e­cules in the body, the risk of side effects from the treat­ments is reduced. It also reduces the effec­tive dose, and there­fore the total cost of treatment.

The price of bio­ther­a­pies and there­fore of RNA is a major issue. In the case of anti-covid vac­cines, the dos­es of RNA required are small. Larg­er quan­ti­ties of bio­mol­e­cules will be need­ed for can­cer appli­ca­tions. As is often the case with bio­med­ical inno­va­tions, it will be a ques­tion of find­ing a bal­ance between the financ­ing of phar­ma­ceu­ti­cal research, pro­duc­tion costs and the acces­si­bil­i­ty of prod­ucts for all. The glob­al phar­ma­ceu­ti­cal mar­ket as a whole is cur­rent­ly worth more than $1,300bn. If the new biotech­nolo­gies cov­ered all needs, this mar­ket would be worth $4,800bn, which is not sus­tain­able for our health sys­tems. The phar­ma­ceu­ti­cal indus­try is aware that it will not be able to sell inno­v­a­tive ther­a­peu­tic prod­ucts tomor­row if this trend con­tin­ues. The finan­cial issue is there­fore crit­i­cal to the suc­cess of future of biotherapies.

To meet this chal­lenge of acces­si­bil­i­ty to inno­v­a­tive ther­a­pies, the research com­mu­ni­ty and indus­try are work­ing to devel­op tech­nolo­gies with more eco­nom­i­cal pro­duc­tion while guar­an­tee­ing patient safe­ty. France wants to be a major play­er in this sec­tor and the State sup­ports this sec­tor with­in the frame­work of its Strat­e­gy for Accel­er­at­ing Bio­ther­a­pies and Bio­pro­duc­tion of Inno­v­a­tive Ther­a­pies financed via the Future Invest­ment Pro­gramme and announced by the Pres­i­dent of the Repub­lic dur­ing his speech on the Health Inno­va­tion 2030 plan.

* The France Recov­ery Plan is a set of invest­ments, to the tune of €100bn, sup­port­ed by the Euro­pean Union with fund­ing of approx­i­mate­ly €40bn, deployed by the Gov­ern­ment since 2020 around three com­po­nents: eco­log­i­cal tran­si­tion, com­pet­i­tive­ness and cohe­sion. This plan was set in motion with a view to rapid­ly reviv­ing the econ­o­my and obtain­ing results in terms of decar­bon­i­sa­tion, indus­tri­al recon­quest, and the strength­en­ing of skills and qual­i­fi­ca­tions through­out the country.