Promis­ing mR­NA tech comes with reg­u­la­to­ry, CMC headaches

As the buzz builds around mes­sen­ger RNA (mR­NA) tech­nol­o­gy’s use for two lead­ing Covid-19 can­di­dates, man­u­fac­tur­ers and reg­u­la­to­ry pro­fes­sion­als are fac­ing facts: This is not sim­ple tech­nol­o­gy.

Com­plex man­u­fac­tur­ing process­es, de­liv­ery ve­hi­cles that must be treat­ed more as drug sub­stances than ex­cip­i­ents, and po­ten­tial im­muno­genic­i­ty headaches are among the chal­lenges in­dus­try faces as this promis­ing tech­nol­o­gy is har­nessed to ad­dress an in­creas­ing num­ber of health con­di­tions.

Tra­cy Mef­fen

At Oc­to­ber’s vir­tu­al Eu­ro Con­ver­gence con­fer­ence, Tra­cy Mef­fen, VP for qual­i­ty and reg­u­la­to­ry af­fairs at Gen­event Sci­ences Cor­po­ra­tion, walked at­ten­dees through the ba­sics of the tech­nol­o­gy, plac­ing fo­cus on chem­istry, man­u­fac­tur­ing and con­trol (CMC) con­sid­er­a­tions from a reg­u­la­to­ry af­fairs per­spec­tive.

Two types of RNA ther­a­peu­tics work in dif­fer­ent ways to cre­ate op­pos­ing ef­fects, ex­plained Mef­fen. By car­ry­ing ge­net­ic in­for­ma­tion in sin­gle-strand­ed RNA that en­ables pro­tein syn­the­sis, mR­NA ther­a­peu­tics up-reg­u­late pro­teins that are faulty or miss­ing. In con­trast, the dou­ble-strand­ed RNA strands of siR­NA ther­a­peu­tics de­grade mR­NA af­ter tran­scrip­tion, there­by pre­vent­ing trans­la­tion and elim­i­nat­ing ex­ces­sive pro­teins that cause dis­ease be­cause they are faulty or over­abun­dant.

Mes­sen­ger RNA is con­sid­ered by both the FDA and the EMA to be gene ther­a­py “even though RNA does not in­ter­act with the genome,” said Mef­fen in giv­ing a reg­u­la­to­ry overview of the two types of RNA ther­a­pies. How­ev­er, mR­NA, which is reg­u­lat­ed by the FDA’s Cen­ter for Bi­o­log­ics Eval­u­a­tion and Re­search (CBER) is not yet clas­si­fied as a re­gen­er­a­tive med­i­cine ad­vanced ther­a­py (RMAT). EMA con­sid­ers mR­NA to be an ad­vanced ther­a­py med­i­c­i­nal prod­uct (ATMP).

Nei­ther FDA nor EMA con­sid­er siR­NAs to be gene ther­a­py. “FDA reg­u­lates them as a drug, not a bi­o­log­ic, and they are not an ATMP,” ex­plained Mef­fen; siR­NA ther­a­pies do not have RMAT sta­tus. For both types of RNA ther­a­pies, spon­sors should be aware of the va­ri­ety of reg­u­la­to­ry pro­grams avail­able for rare ge­net­ic dis­or­ders, she not­ed.

In terms of the nuts and bolts of RNA ther­a­peu­tics, the key bar­ri­er is de­liv­ery; get­ting both mR­NA and siR­NA across the cell mem­brane is chal­leng­ing. Two ways that have been de­vel­oped to achieve de­liv­ery are the use of lipid nanopar­ti­cles (LNPs) to en­vel­op the nu­cle­ic acid — a tech­nique that can be used with both types of RNA ther­a­peu­tics — and us­ing N-acetyl­galac­tosamine (GalNAc) link­er chem­istry to sta­bi­lize siR­NA and en­hance cel­lu­lar de­liv­ery. While the lipid nanopar­ti­cle tech­nol­o­gy is be­ing used for mR­NA Covid-19 vac­cine can­di­dates, “A key ad­van­tage of the GalNAc tech­nol­o­gy is that it can be used to in­ject siR­NA sub­cu­ta­neous­ly,” said Mef­fen.

Po­ten­tial clin­i­cal ap­pli­ca­tions for the two RNA ther­a­peu­tics abound; mR­NA is be­ing in­ves­ti­gat­ed for vac­cines against oth­er virus­es in ad­di­tion to Covid-19, as well as for can­cer vac­cines and rare ge­net­ic dis­or­ders in­clud­ing cys­tic fi­bro­sis. On the siR­NA side, on­go­ing re­search is look­ing at the tech­nol­o­gy for he­pati­tis B virus treat­ment, and for a va­ri­ety of rare ge­net­ic dis­or­ders. The first two siR­NA ther­a­pies have re­cent­ly been ap­proved in the U and Eu­rope for acute he­pat­ic por­phyr­ia and hAT­TR amy­loi­do­sis, not­ed Mef­fen.

In terms of CMC con­sid­er­a­tions, most LNP for­mu­la­tions re­quire par­enter­al or bo­lus in­tra­mus­cu­lar de­liv­ery. “The lipids that make up an LNP are more func­tion­al than a sim­ple ex­cip­i­ent, so need to be syn­the­sized and con­trolled to a high grade and will need to be ad­e­quate­ly de­scribed in reg­u­la­to­ry fil­ings,” ex­plained Mef­fen. The like­ly need for frozen stor­age adds com­plex­i­ty on the dis­tri­b­u­tion side, she added.

“Step­ping back to the mR­NA drug sub­stance, man­u­fac­tur­ing and test­ing are spe­cial­ized, and scale-up can be chal­leng­ing,” she said. Im­muno­genic re­sponse is pos­si­ble with mR­NA ther­a­pies for rare dis­eases, so man­u­fac­tur­ers and reg­u­la­to­ry pro­fes­sion­als must be vig­i­lant at all stages, since even small vari­a­tions in man­u­fac­tur­ing can have an im­pact on im­muno­genic­i­ty. Man­u­fac­tur­ing siR­NA prod­ucts is a “very ex­pen­sive” process that can take from 4 to 6 weeks. “Ex­per­tise in man­u­fac­tur­ing and test­ing siR­NA is es­sen­tial, said Mef­fen. If the fin­ished prod­uct is a liq­uid for­mu­la­tion, it will need care­ful han­dling dur­ing trans­porta­tion to avoid caus­ing changes in phys­i­cal char­ac­ter­is­tics.

In ad­di­tion to the usu­al drug qual­i­ty at­trib­ut­es, mR­NA drug sub­stances have a unique set of at­trib­ut­es to con­sid­er, in­clud­ing mR­NA in­tegri­ty and con­cen­tra­tion, resid­ual DNA tem­plate and resid­ual dou­ble-strand­ed DNA, said Mef­fen. Qual­i­ty at­trib­ut­es spe­cif­ic to siR­NA prod­ucts in­clude iden­ti­fi­ca­tion and pu­ri­ty con­trol of both the sense-an­ti­sense du­plex and the in­di­vid­ual sin­gle strands.


RAPS: First pub­lished in Reg­u­la­to­ry Fo­cus™ by the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety, the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care prod­ucts. Click here for more in­for­ma­tion.

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