Lewis, L. M., Badkar, A. V., Cirelli, D., Combs, R. & Lerch, T. F. The race to develop the Pfizer–BioNTech COVID-19 vaccine: from the pharmaceutical scientists’ perspective. J. Pharm. Sci. 112, 640–647 (2023).
Thorn, C. R. et al. The journey of a lifetime — growth of Pfizer’s COVID-19 vaccine. Curr. Opin. Biotechnol. 78, 102803 (2022).
Warne, N. et al. Delivering 3 billion doses of Comirnaty in 2021. Nat. Biotechnol. 41, 183–188 (2023).
Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA supply. Nat. Rev. Mater. 6, 1078–1094 (2021).
Cullis, P. R. & Hope, M. J. Lipid nanoparticle methods for enabling gene therapies. Mol. Ther. 25, 1467–1475 (2017). A foundational assessment article that explains the basic design ideas for LNPs and their proposed mechanism of motion.
Swaminathan, G. et al. A novel lipid nanoparticle adjuvant considerably enhances B cell and T cell responses to sub-unit vaccine antigens. Vaccine 34, 110–119 (2016).
Zhang, Y., Solar, C., Wang, C., Jankovic, Okay. E. & Dong, Y. Lipids and lipid derivatives for RNA supply. Chem. Rev. 121, 12181–12277 (2021). An exhaustive assessment of lipids which were utilized in LNPs for nucleic acid supply, with an outline of the design ideas for every lipid class.
Hald Albertsen, C. et al. The function of lipid elements in lipid nanoparticles for vaccines and gene remedy. Adv. Drug Deliv. Rev. 188, 114416 (2022).
Cheng, Q. et al. Selective organ concentrating on (SORT) nanoparticles for tissue-specific mRNA supply and CRISPR–Cas gene modifying. Nat. Nanotechnol. 15, 313–320 (2020).
Steering for Business: Nonclinical Research for the Security Analysis of Pharmaceutical Excipients (US FDA, 2005); https://www.fda.gov/media/72260/obtain
Guideline on Excipients within the File for Utility for Advertising Authorisation of a Medicinal Product EMEA/CHMP/QWP/396951/2006 (EMA, 2007); https://www.ema.europa.eu/en/paperwork/scientific-guideline/guideline-excipients-dossier-application-marketing-authorisation-medicinal-product-revision-2_en.pdf
Elder, D. P., Kuentz, M. & Holm, R. Pharmaceutical excipients — high quality, regulatory and biopharmaceutical issues. Eur. J. Pharm. Sci. 87, 88–99 (2016).
Kozarewicz, P. & Loftsson, T. Novel excipients – regulatory challenges and views – the EU perception. Int. J. Pharm. 546, 176–179 (2018).
Koo, O. M. & Varia, S. A. Case research with new excipients: growth, implementation and regulatory approval. Ther. Deliv. 2, 949–956 (2011).
Yu, Y. B., Taraban, M. B., Briggs, Okay. T., Brinson, R. G. & Marino, J. P. Excipient innovation by means of precompetitive analysis. Pharm. Res. 38, 2179–2184 (2021).
John, R., Monpara, J., Swaminathan, S. & Kalhapure, R. Chemistry and artwork of creating lipid nanoparticles for biologics supply: concentrate on growth and scale-up. Pharmaceutics 16, 131 (2024).
Onpattro (Patisiran) Lipid Advanced Injection, for Intravenous Use [Package Insert] (US FDA, 2018); https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/210922s012lbl.pdf
Committee for Medicinal Merchandise for Human Use. Onpattro Evaluation Report EMA/554262/2018 (EMA, 2018); https://www.ema.europa.eu/en/paperwork/assessment-report/onpattro-epar-public-assessment-report_.pdf
Drug Approval Package deal: Onpattro (patisiran) (US FDA, 2018); https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210922Orig1s000TOC.cfm. The drug approval bundle for Onpattro—an LNP permitted by the US FDA for industrial use, and the one one by way of the NDA pathway.
Abstract Foundation for Regulatory Motion: Comirnaty (US FDA, 2021); https://www.fda.gov/media/151733/obtain. The abstract foundation of approval for Comirnaty—the second LNP permitted (by way of emergency-use authorization) by the US FDA for industrial use, this time by way of the BLA pathway.
Comirnaty (COVID-19 Vaccine, mRNA) Suspension for Injection, for Intramuscular Use [Package Insert] (US FDA, 2021); https://www.fda.gov/media/151707/obtain
Committee for Medicinal Merchandise for Human Use. Comirnaty Evaluation Report EMA/707383/2020 Corr.2 (EMA, 2021); https://www.ema.europa.eu/en/paperwork/assessment-report/comirnaty-epar-public-assessment-report_en.pdf
Spikevax (COVID-19 Vaccine, mRNA) Suspension for Injection, for Intramuscular Use [Package Insert] (US FDA, 2022); https://www.fda.gov/media/155675/obtain
Abstract Foundation for Regulatory Motion: Spikevax (US FDA, 2022); https://www.fda.gov/media/155931/obtain. The abstract foundation of approval for Spikevax—the third LNP permitted (by way of emergency-use authorization) by the US FDA for industrial use, and the second by way of the BLA pathway.
Committee for Medicinal Merchandise for Human Use. COVID-19 Vaccine Moderna Evaluation Report EMA/15689/2021 Corr.1 (EMA, 2021); https://www.ema.europa.eu/en/paperwork/assessment-report/spikevax-previously-covid-19-vaccine-moderna-epar-public-assessment-report_en.pdf
Hemmrich, E. & McNeil, S. Lively ingredient vs excipient debate for nanomedicines. Nat. Nanotechnol. 18, 692–695 (2023). A perspective that highlights the inconsistency in how elements inside nanomedicines could also be labeled as excipients or part of the energetic ingredient.
Steering for Business: Liposome Drug Merchandise (US FDA, 2018); https://www.fda.gov/media/70837/obtain. Probably the most complete regulatory steerage doc on lipid excipients, with a concentrate on their use in liposome drug merchandise.
Committee for Medicinal Merchandise for Human Use. Guideline on the Chemistry of Lively Substances EMA/454576/2016 (EMA, 2016); https://www.ema.europa.eu/en/paperwork/scientific-guideline/guideline-chemistry-active-substances_en.pdf
Committee for Human Medicinal Merchandise. Reflection Paper on the Knowledge Necessities for Intravenous Liposomal Merchandise Developed with Reference to an Innovator Liposomal Product EMA/CHMP/806058/2009/Rev. 02 (EMA, 2013); https://www.ema.europa.eu/en/paperwork/scientific-guideline/reflection-paper-data-requirements-intravenous-liposomal-products-developed-reference-innovator_en.pdf
Analysis of the High quality, Security and Efficacy of Messenger RNA Vaccines for the Prevention of Infectious Ailments: Regulatory Issues (World Well being Group, 2021); https://cdn.who.int/media/docs/default-source/biologicals/ecbs/post-ecbs-who-regulatory-considerations-document-for-mrna-vaccines—final-version—29-nov-2021_tz.pdf. The regulatory steerage doc that the majority particularly outlines CMC expectations for LNPs, albeit not from a well being authority liable for the approval of scientific or industrial submitting functions.
Qualification of Excipients for Use in Prescription drugs (Worldwide Pharmaceutical Excipients Council, 2020); https://www.ipec-europe.org/uploads/publications/20201026-eq-guide-revision-final-1615800052.pdf
The Joint Good Manufacturing Practices Information for Pharmaceutical Excipients Model 5 (Worldwide Pharmaceutical Excipients Council, Pharmaceutical High quality Group, 2022); https://www.ipec-europe.org/articles/ipec-pqg-gmp-guide.html
Schoenmaker, L. et al. mRNA-lipid nanoparticle COVID-19 vaccines: construction and stability. Int. J. Pharm. 601, 120586 (2021).
Oude Blenke, E. et al. The storage and in-use stability of mRNA vaccines and therapeutics: not a chilly case. J. Pharm. Sci. 112, 386–403 (2023).
Musakhanian, J., Rodier, J.-D. & Dave, M. Oxidative stability in lipid formulations: a assessment of the mechanisms, drivers, and inhibitors of oxidation. AAPS PharmSciTech 23, 151 (2022).
De, A. & Ko, Y. T. Why mRNA-ionizable LNPs formulations are so short-lived: causes and way-out. Skilled Opin. Drug Deliv. 20, 175–187 (2023).
Wang, C., Gamage, P. L., Jiang, W. & Mudalige, T. Excipient-related impurities in liposome drug merchandise. Int. J. Pharm. 657, 124164 (2024).
Kleintop, B. et al. GMPs for methodology validation in early growth: an {industry} perspective (half II). Pharm. Technol. https://www.pharmtech.com/view/gmps-method-validation-early-development-industry-perspective-part-ii (2012).
Harvey, J. et al. Administration of natural impurities in small molecule medicinal merchandise: deriving protected limits to be used in early growth. Regul. Toxicol. Pharmacol. 84, 116–123 (2017). A commentary that outlines impurity management methods which may be utilized in early scientific growth, which can be thought of for lipid excipients in LNPs.
Steering for Business: Q3A Impurities in New Drug Substances (US FDA, 2008); https://www.fda.gov/media/71727/obtain
Steering for Business: M4Q: The CTD — High quality (US FDA, 2001); https://www.fda.gov/media/71581/obtain
Steering for Business: Drug Grasp Information (US FDA, 2019); https://www.fda.gov/media/131861/obtain
Biologics license functions and grasp recordsdata. Fed. Reg. 89, 9743–9757 (12 February 2024); https://www.govinfo.gov/content material/pkg/FR-2024-02-12/pdf/2024-02741.pdf
Steering for Business: Q2(R2) Validation of Analytical Procedures (US FDA, 2022); https://www.fda.gov/media/161201/obtain
Steering for Business: Q3C Impurities: Residual Solvents (US FDA, 1997); https://www.fda.gov/media/71736/obtain
Steering for Business: Q3D(R2) Elemental Impurities (US FDA, 2022); https://www.fda.gov/media/148474/obtain
Steering for Business: Management of Nitrosamine Impurities in Human Medication (US FDA, 2021); https://www.fda.gov/media/141720/obtain
Raffaele, J., Loughney, J. W. & Rustandi, R. R. Improvement of a microchip capillary electrophoresis methodology for willpower of the purity and integrity of mRNA in lipid nanoparticle vaccines. Electrophoresis 43, 1101–1106 (2022).
Packer, M., Gyawali, D., Yerabolu, R., Schariter, J. & White, P. A novel mechanism for the lack of mRNA exercise in lipid nanoparticle supply methods. Nat. Commun. 12, 6777 (2021). An progressive analysis article that highlighted how reactions between a nucleic acid and lipid in an LNP can impression product high quality and manufacturing management methods.
Kinsey, C. et al. Willpower of lipid content material and stability in lipid nanoparticles utilizing extremely high-performance liquid chromatography together with a corona charged aerosol detector. Electrophoresis 43, 1091–1100 (2022).
Wei, T., Cheng, Q., Min, Y.-L., Olson, E. N. & Siegwart, D. J. Systemic nanoparticle supply of CRISPR–Cas9 ribonucleoproteins for efficient tissue particular genome modifying. Nat. Commun. 11, 3232 (2020).
Kasiewicz, L. N. et al. GalNAc-Lipid nanoparticles allow non-LDLR dependent hepatic supply of a CRISPR base modifying remedy. Nat. Commun. 14, 2776 (2023).
Dilliard, S. A. & Siegwart, D. J. Passive, energetic and endogenous organ-targeted lipid and polymer nanoparticles for supply of genetic medicine. Nat. Rev. Mater. 8, 282–300 (2023).
Lokugamage, M. P. et al. Optimization of lipid nanoparticles for the supply of nebulized therapeutic mRNA to the lungs. Nat. Biomed. Eng. 5, 1059–1068 (2021).
Steering for Business: Chemistry, Manufacturing, and Management (CMC) Data for Human Gene Remedy Investigational New Drug Purposes (INDs) (US FDA, 2020); https://www.fda.gov/media/113760/obtain
Steering for Business: Drug Merchandise, Together with Organic Merchandise, that Comprise Nanomaterials (US FDA, 2022); https://www.fda.gov/media/157812/obtain
Guideline for the Improvement of Liposome Drug Merchandise (Japan Ministry of Well being, Labour and Welfare, 2016); https://www.nihs.go.jp/drug/section4/160328_MHLW_liposome_guideline.pdf
Reflection Paper on Nucleic Acids (siRNA)-loaded Nanotechnology-based Drug Merchandise (Japan Ministry of Well being, Labour and Welfare, 2016); https://www.nihs.go.jp/drug/section4/160328_MHLW_siRNA_RP.pdf
Wasylaschuk, W. R. et al. Analysis of hydroperoxides in frequent pharmaceutical excipients. J. Pharm. Sci. 96, 106–116 (2007).
Garner, J. et al. A protocol for assay of poly(lactide-co-glycolide) in scientific merchandise. Int. J. Pharm. 495, 87–92 (2015).
Yanez Arteta, M. et al. Profitable reprogramming of mobile protein manufacturing by means of mRNA delivered by functionalized lipid nanoparticles. Proc. Natl Acad. Sci. USA 115, E3351–E3360 (2018).
Suzuki, Y. & Ishihara, H. Distinction within the lipid nanoparticle expertise employed in three permitted siRNA (Patisiran) and mRNA (COVID-19 vaccine) medicine. Drug. Metab. Pharmacokinet. 41, 100424 (2021).
Cheng, X. & Lee, R. J. The function of helper lipids in lipid nanoparticles (LNPs) designed for oligonucleotide supply. Adv. Drug Deliv. Rev. 99, 129–137 (2016).
Kulkarni, J. A., Witzigmann, D., Leung, J., Tam, Y. Y. C. & Cullis, P. R. On the function of helper lipids in lipid nanoparticle formulations of siRNA. Nanoscale 11, 21733–21739 (2019).
Zhang, R. et al. Helper lipid construction influences protein adsorption and supply of lipid nanoparticles to spleen and liver. Biomater. Sci. 9, 1449–1463 (2021).
Álvarez-Benedicto, E. et al. Optimization of phospholipid chemistry for improved lipid nanoparticle (LNP) supply of messenger RNA (mRNA). Biomater. Sci. 10, 549–559 (2022).
Patel, S. et al. Naturally-occurring ldl cholesterol analogues in lipid nanoparticles induce polymorphic form and improve intracellular supply of mRNA. Nat. Commun. 11, 983 (2020).
Paunovska, Okay. et al. Nanoparticles containing oxidized ldl cholesterol ship mRNA to the liver microenvironment at clinically related doses. Adv. Mater. 31, 1807748 (2019).
Li, Z. et al. Acidification-induced construction evolution of lipid nanoparticles correlates with their in vitro gene transfections. ACS Nano 17, 979–990 (2023).
Francia, V., Schiffelers, R. M., Cullis, P. R. & Witzigmann, D. The biomolecular corona of lipid nanoparticles for gene remedy. Bioconjug. Chem. 31, 2046–2059 (2020).
Hoang Thi, T. T. et al. The significance of poly(ethylene glycol) options for overcoming PEG immunogenicity in drug supply and bioconjugation. Polymers 12, 298 (2020).
Nogueira, S. S. et al. Polysarcosine-functionalized lipid nanoparticles for therapeutic mRNA supply. ACS Appl. Nano Mater. 3, 10634–10645 (2020).
Shi, D. et al. To PEGylate or to not PEGylate: immunological properties of nanomedicine’s hottest part, polyethylene glycol and its options. Adv. Drug Deliv. Rev. 180, 114079 (2022).
Abu Lila, A. S., Kiwada, H. & Ishida, T. The accelerated blood clearance (ABC) phenomenon: scientific problem and approaches to handle. J. Management. Launch 172, 38–47 (2013).
Chen, B.-M., Cheng, T.-L. & Roffler, S. R. Polyethylene glycol immunogenicity: theoretical, scientific, and sensible facets of anti-polyethylene glycol antibodies. ACS Nano 15, 14022–14048 (2021).
Ju, Y. et al. Anti-PEG antibodies boosted in people by SARS-CoV-2 lipid nanoparticle mRNA vaccine. ACS Nano 16, 11769–11780 (2022).
Bavli, Y. et al. Anti-PEG antibodies earlier than and after a primary dose of Comirnaty® (mRNA-LNP-based SARS-CoV-2 vaccine). J. Management. Launch 354, 316–322 (2023).
Münter, R. et al. Investigating era of antibodies towards the lipid nanoparticle vector following COVID-19 vaccination with an mRNA vaccine. Mol. Pharm. 20, 3356–3366 (2023).
Semple, S. C. et al. Rational design of cationic lipids for siRNA supply. Nat. Biotechnol. 28, 172–176 (2010).
Jayaraman, M. et al. Maximizing the efficiency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chem. Int. Ed. 51, 8529–8533 (2012).
Han, X. et al. An ionizable lipid toolbox for RNA supply. Nat. Commun. 12, 7233 (2021).
Carrasco, M. J. et al. Ionization and structural properties of mRNA lipid nanoparticles affect expression in intramuscular and intravascular administration. Commun. Biol. 4, 956 (2021).
Hajj, Okay. A. et al. Branched-tail lipid nanoparticles potently ship mRNA in vivo resulting from enhanced ionization at endosomal pH. Small 15, 1805097 (2019).
Han, X. et al. In situ combinatorial synthesis of degradable branched lipidoids for systemic supply of mRNA therapeutics and gene editors. Nat. Commun. 15, 1762 (2024).
Bhatia, S. N. & Dahlman, J. E. RNA supply methods. Proc. Natl Acad. Sci. USA 121, e2315789121 (2024).
Wittrup, A. et al. Visualizing lipid-formulated siRNA launch from endosomes and goal gene knockdown. Nat. Biotechnol. 33, 870–876 (2015).
Cornebise, M. et al. Discovery of a novel amino lipid that improves lipid nanoparticle efficiency by means of particular interactions with mRNA. Adv. Func. Mater. 32, 2106727 (2022).
Da Silva Sanchez, A. J. et al. Substituting racemic ionizable lipids with stereopure ionizable lipids can enhance mRNA supply. J. Management. Launch 353, 270–277 (2023).
Jörgensen, A. M., Wibel, R. & Bernkop-Schnürch, A. Biodegradable cationic and ionizable cationic lipids: a roadmap for safer pharmaceutical excipients. Small 19, 2206968 (2023).
Ci, L. et al. Biodistribution of Lipid 5, mRNA, and its translated protein following intravenous administration of mRNA-encapsulated lipid nanoparticles in rats. Drug Metab. Dispos. 51, 813–823 (2023).
Burdette, D. et al. Systemic publicity, metabolism, and elimination of [14C]-labeled amino lipid, Lipid 5, after a single administration of mRNA encapsulating lipid nanoparticles to Sprague-Dawley rats. Drug Metab. Dispos. 51, 804–812 (2023).
Zhang, X., Goel, V. & Robbie, G. J. Pharmacokinetics of patisiran, the primary permitted RNA interference remedy in sufferers with hereditary transthyretin-mediated amyloidosis. J. Clin. Pharmacol. 60, 573–585 (2020).
Gregoriadis, G. (ed.) Liposome Know-how: Entrapment of Medication and Different Supplies into Liposomes third edn (CRC, 2006).
Allen, T. M. & Cullis, P. R. Liposomal drug supply methods: from idea to scientific functions. Adv. Drug Deliv. Rev. 65, 36–48 (2013).
Barenholz, Y. Doxil®—the primary FDA-approved nano-drug: classes realized. J. Management. Launch 160, 117–134 (2012).
Immordino, M. L., Dosio, F. & Cattel, L. Stealth liposomes: assessment of the fundamental science, rationale, and scientific functions, current and potential. Int. J. Nanomedicine 1, 297–315 (2006).
Chen, M.-L. Lipid excipients and supply methods for pharmaceutical growth: a regulatory perspective. Adv. Drug Deliv. Rev. 60, 768–777 (2008).
Mui, B. L. et al. Affect of polyethylene glycol lipid desorption charges on pharmacokinetics and pharmacodynamics of siRNA lipid nanoparticles. Mol. Ther. Nucleic Acids 2, e139 (2013).
Ldl cholesterol. In US Pharmacopeia USP29–NF24, 3314 (United States Pharmacopeial Conference, 2007).
Ldl cholesterol. In Japanese Pharmacopeia 18th edn, 749 (The Prescription drugs and Medical Units Company, 2021).
Ldl cholesterol. In European Pharmacopoeia 7.0 1680–1681 (European Directorate for the High quality of Medicines & HealthCare (EDQM), 2008).
Ldl cholesterol for parenteral use. In European Pharmacopoeia 8.0 1874 (EDQM, 2012).
Ldl cholesterol for parenteral use. In European Pharmacopoeia 10.0 2397E (EDQM, 2020).
Ldl cholesterol for parenteral use. In European Pharmacopoeia 11.0 2397 (EDQM, 2023).
