Issue link: https://www.e-digitaleditions.com/i/1375981
www.biopharminternational.com May 2021 BioPharm International eBook 9 ma nu fac t u re add s t he add it ion a l complexity of the requirement to use dedicated cleanrooms and the provi- sion of GMP documentation, includ- ing a Cer t i f icate of A na ly sis a nd Certif icate of Conformity signed off by an appropriately qualified person. The manufacturing process used at eTheRNA is in-vitro transcription (IV T). The IV T production step is preceded by synthesis of DNA for the sequence of interest, plasmid clon- ing and purif ication, linea rization of the plasmid, and its purif ication and characterization, and is followed by the in-vitro transcription reaction and the purif ication and characteri- zation of the RNA, bioburden reduc- tion or sterile f iltration, and f inally analysis, according to the pre-agreed requirements of the project. C ompa n ie s t y pic a l ly out sou rce RNA manufacture for either strategic or tactical reasons. Given that GMP manufacture is a complex and regu- lated process, it is expensive and slow to establish in house, and requires a combination of expertise, equipment, and established processes that must be approved by regulator y authori- ties before GMP manufact ure can begin. A smaller company or institu- tion might make the strategic deci- sion to outsource RNA manufacture if RNA production in-house is not a core competence and, if it would be a steep learning curve, for f inan- cial reasons, or because the required e x per t ise is si mply not av a i lable. Groups may take a tactical decision to outsource if their internal manu- facturing capability is at capacity, or if it is more cost effective or quicker to outsource than produce internally. Based on experiences at eTheRNA, we have seen that it is benef icia l to work with groups at the start of their journey to GMP manufacture. A relationship might start with the manufacture of a small quantit y of research-grade RNA, for initial bio- logical assessment of the RNA, or, for example, for preclinical toxicit y studies. Starting a relationship early allows for optimization of procedures without recourse to the restrictions necessitated by GMP and enables pro- cesses to be developed and optimized with larger-scale GMP manufacture in mind. RAPID AND LONG-TERM GROWTH BioPharm: W hy is R NA cont ract manufacturing experiencing growth, and do you believe the growth will continue in the longer term? Ricketts (eTheRNA): Just as anti- body and other protein therapeutics came to the fore as a new therapeutic moda lit y in the 1990s/20 0 0s (and protein t herapeut ics now accou nt for ov e r 2 5% of F DA ap prov a l s over the past f ive years [5]), we are now faced with additional modali- ties in the form of a range of RNA/ DNA and cell-based therapies and vaccines. Over time, each modalit y will f ind its own niche where it is particularly relevant for deployment, but we a re now at t he pioneer ing early-adopter phase of R NA based therapies, and vaccines in particu- la r, where many oppor t unities a re being explored. R NA is of specia l interest now due to the successful and extremely rapid development of RNA vaccines aga inst the SA R S-Cov-2 virus by BioNTech/Pf izer, CureVac, and Moderna, but also because of the specific biological role of RNA itself. While the DNA sequence of each cell is (generally and arguably) static, the RNA complement of a cell var- ies over time, in response to disease, treatment, and other external stim- uli. While the old biochemical adage 'DNA makes R NA makes protein' broad ly st i l l holds t r ue, it is now known that different types of RNA are involved in cellular regulatory and feedback systems—it is not only the message written in messenger RNA (mRNA) that def ines cellular func- tion. Therapeutic modalities that can inter vene, for example, in a disease process offer the opportunit y for a therapeutic to be exquisitely selec- tive even down to the level of a spe- cif ic cell type—offering benef its of reduced side effects and lower dosage. Fur ther, R NA is a key stage in [clustered regularly interspaced short palindromic repeats] CR ISPR-Cas9 based gene editing and in [chime- r ic a nt igen receptor] CA R-T cel l a nd [T-cel l receptor] TCR t hera- pies. The ubiquitous need for RNA in these approaches, and as thera- peutics and vaccines in themselves ma ke R NA , mea ns t hat t he need for RNA manufacture is poised for significant growth. F i n a l l y, R N A m o l e c u l e s a r e known to be less stable than DNA, a nd t hei r succe s sf u l use dep ends upon special deliver y vehicles, t yp- ica l ly lipid nano par ticles (LNPs), which protect them from degrada- tion until their payload reaches the desi red cel lu la r locat ion a nd a lso del ivers t hem into t he cel l. LN P technolog y has moved for ward sig- nif icant ly over t he past few yea rs a nd, as t he BioN Tech / Pf iz er a nd Moderna vaccines have illustrated, the technology works well and can be deployed rapidly and at scale. For these reasons, we believe that the use of RNA as therapeutics and vaccines as we see it now is not just in its infancy, it is at an embryonic stage. We foresee rapid grow th in the application of RNA based thera- peutics and vaccines and believe that over t he ne x t decade R NA based products w i l l ta ke a n equa l place alongside small molecule and protein therapeutics. SERVICE EXPANSION CONSIDERATIONS BioPharm: What sort of challenges face companies look ing to expand contract services beyond research and into broader capabilities? Partnerships for Outsourcing Manufacturing