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Volume 20, Issue 2
  • ISSN: 1574-8855
  • E-ISSN: 2212-3903

Abstract

Biopharmaceuticals differ significantly from chemical drugs, and thus their CMC regulatory compliance is distinct from them. The development of biologicals, like mRNA vaccines, holds promise for preventing infectious diseases and generating an antigen-specific immune response. These vaccines are a better option than traditional vaccination methods because of their significant potency and swift and affordable manufacture. The compliance strategy is shaped by evaluating resource allocation and risk tolerance. This review examines the CMC regulatory requirements concerned with the manufacturing of biologics, particularly mRNA vaccines. The many challenges that could arise when producing biological products are also discussed in this paper, like the introduction of adventitious agents that can affect the safety of the product and the molecular designs of mRNA molecules, which may need to be optimized for higher protein expression and improved structural stability. By implementing the Quality by Design approach during the development, a better understanding of the controls and risk management should be utilized to minimize the risk and improve compliance.

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2024-02-02
2024-12-28

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References

  1. AreW. What are “Biologics” questions and answers FDAAvailable from: https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers
    [Google Scholar]
  2. History of Measles CDCAvailable from: https://www.cdc.gov/measles/about/history.html
  3. AndreF.E. BooyR. BockH.L. Vaccination greatly reduces disease, disability, death and inequity worldwide.Bull. World Health Organ.200886214014610.2471/BLT.07.040089 18297169
     [Google Scholar]
  4. AmannaI.J. SlifkaM.K. Successful vaccines.Curr. Top. Microbiol. Immunol.2020428130 30046984
     [Google Scholar]
  5. A brief history of vaccinationAvailable from: https://www.who.int/news-room/spotlight/history-of-vaccination/abrief-history-of-vaccination
  6. WolffJ.A. MaloneR.W. WilliamsP. Direct gene transfer into mouse muscle in vivo.Science199024749491465146810.1126/science.1690918 1690918
     [Google Scholar]
  7. LjungbergK. LiljeströmP. Self-replicating alphavirus RNA vaccines.Expert Rev. Vaccines201514217719410.1586/14760584.2015.965690
     [Google Scholar]
  8. RossJ. mRNA stability in mammalian cells.Microbiol. Rev.199559342345010.1128/mr.59.3.423‑450.1995 7565413
     [Google Scholar]
  9. KwonS. KwonM. ImS. LeeK. LeeH. mRNA vaccines: The most recent clinical applications of synthetic mRNA.Arch. Pharm. Res.202245424526210.1007/s12272‑022‑01381‑7 35426547
     [Google Scholar]
  10. JacksonN.A.C. KesterK.E. CasimiroD. GurunathanS. DeRosaF. The promise of mRNA vaccines: A biotech and industrial perspective.NPJ Vaccines2020511110.1038/s41541‑020‑0159‑8 32047656
     [Google Scholar]
  11. PardiN. HoganM.J. PorterF.W. WeissmanD. mRNA vaccines — a new era in vaccinology.Nat. Rev. Drug Discov.201817426127910.1038/nrd.2017.243 29326426
     [Google Scholar]
  12. WickensM. How the messenger got its tail: Addition of poly(A) in the nucleus.Trends Biochem. Sci.199015727728110.1016/0968‑0004(90)90054‑F 1974368
     [Google Scholar]
  13. SchlakeT. ThessA. Fotin-MleczekM. KallenK.J. Developing mRNA-vaccine technologies.RNA Biol.20121391319133010.4161/rna.22269
     [Google Scholar]
  14. SahinU. KarikóK. TüreciÖ. mRNA-based therapeutics — developing a new class of drugs.Nat. Rev. Drug Discov.2014131075978010.1038/nrd4278 25233993
     [Google Scholar]
  15. KisZ. KontoravdiC. ShattockR. ShahN. Resources, production scales and time required for producing RNA vaccines for the global pandemic demand.Vaccines202091310.3390/vaccines9010003 33374802
     [Google Scholar]
  16. KarikóK. MuramatsuH. WelshF.A. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability.Mol. Ther.200816111833184010.1038/mt.2008.200 18797453
     [Google Scholar]
  17. KarikóK. MuramatsuH. LudwigJ. WeissmanD. Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, proteinencoding mRNA.Nucleic Acids Res.20113921e14210.1093/nar/gkr695 21890902
     [Google Scholar]
  18. PardiN. ParkhouseK. KirkpatrickE. Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalkspecific antibodies.Nat. Commun.201891336110.1038/s41467‑018‑05482‑0 30135514
     [Google Scholar]
  19. KauffmanK.J. WebberM.J. AndersonD.G. Materials for non-viral intracellular delivery of messenger RNA therapeutics.J. Control. Release201624022723410.1016/j.jconrel.2015.12.032 26718856
     [Google Scholar]
  20. CMC – Chemistry, manufacturing and controls.Pacific BioLabsAvailable from: https://pacificbiolabs.com/cmc-chemistry-manufacturing-and-controls
    [Google Scholar]
  21. Chemistry manufacturing and controls (CMC) guidances for industry (GFIs) and questions and answers (Q&As) FDAAvailable from: https://www.fda.gov/animal-veterinary/guidance-industry/chemistry-manufacturing-and-controls-cmc-guidances-industry-gfis-and-questions-andanswers-qas
  22. WahidR. HoltR. HjorthR. Berlanda ScorzaF. Chemistry, manufacturing and control (CMC) and clinical trial technical support for influenza vaccine manufacturers.Vaccine201634455430543510.1016/j.vaccine.2016.07.046 27484011
     [Google Scholar]
  23. IND applications for clinical investigations: Chemistry, manufacturing, and control (CMC) information FDAAvailable from: https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-applications-clinical-investigations-chemistry-manufacturing-and-control-cmc-information
  24. International council for harmonisation of technical requirements for pharmaceuticals for human use ich harmonised guideline technical and regulatory considerations for pharmaceutical product lifecycle management Q12 final version2019
  25. WebsterC.J. GeorgeK.L. WoollettG.R. Comparability of biologics: Global principles, evidentiary consistency and unrealized reliance.BioDrugs202135437938710.1007/s40259‑021‑00488‑5 34143406
     [Google Scholar]
  26. KirchhoffC.F. WangX.Z.M. ConlonH.D. AndersonS. RyanA.M. BoseA. Biosimilars: Key regulatory considerations and similarity assessment tools.Biotechnol. Bioeng.2017114122696270510.1002/bit.26438 28842986
     [Google Scholar]
  27. Biosimilar comparability exercise - Evidentic GmbHAvailalbe From: https://evidentic.com/biosimilar-comparability-exercise/
  28. mRNA Manufacturing Process | Thermo Fisher Scientific - INAvailalbe From: https://www.thermofisher.com/in/en/home/industrial/pharma-biopharma/nucleic-acid-therapeutic-development-solutions/mrna-therapeutic-resources.html
  29. RosaS.S. PrazeresD.M.F. AzevedoA.M. MarquesM.P.C. mRNA vaccines manufacturing: Challenges and bottlenecks.Vaccine202139162190220010.1016/j.vaccine.2021.03.038 33771389
     [Google Scholar]
  30. McCrackenS. FongN. RosoninaE. 5′-Capping enzymes are targeted to pre-mRNA by binding to the phosphorylated carboxyterminal domain of RNA polymerase II.Genes Dev.199711243306331810.1101/gad.11.24.3306 9407024
     [Google Scholar]
  31. NilsenTW RioDC AresM Jr High-yield synthesis of RNA using T7 RNA polymerase and plasmid DNA or oligonucleotide templates.Cold Spring Harb Protoc2013201311pdb.prot07853510.1101/pdb.prot078535 24184762
     [Google Scholar]
  32. Zobel-RoosS. SteinD. StrubeJ. Evaluation of continuous membrane chromatography concepts with an enhanced process simulation approach.Antibodies2018711310.3390/antib7010013 31544865
     [Google Scholar]
  33. PardiN. MuramatsuH. WeissmanD. KarikóK. In vitro transcription of long RNA containing modified nucleosides.Methods Mol. Biol.2013969294210.1007/978‑1‑62703‑260‑5_2 23296925
     [Google Scholar]
  34. MiaoL. LiL. HuangY. Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation.Nat. Biotechnol.201937101174118510.1038/s41587‑019‑0247‑3 31570898
     [Google Scholar]
  35. DuffyK. Arangundy-FranklinS. HolligerP. Modified nucleic acids: Replication, evolution, and next-generation therapeutics.BMC Biol.202018111210.1186/s12915‑020‑00803‑6 32878624
     [Google Scholar]
  36. mcnallyg Guidance for industry process validation: General principles and practices guidance for industry2011800835
     [Google Scholar]
  37. Medicines Agency EGuideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products.2014Available from: www.ema.europa.eu/contact
  38. Upstream Bioprocessing - From Pre-clinical to ManufacturingBiopharmaceutical Manufacturing | MerckAvailable from: https://www.merckmillipore.com/IN/en/20160926_155350?ReferrerURL=https%3A%2F%2Fwww.google.com%2F
    [Google Scholar]
  39. mAb Downstream ProcessingAvailable from: https://www.sigmaaldrich.com/IN/en/applications/pharmaceutical-and-biopharmaceutical-manufacturing/monoclonal-antibody-manufacturing/downstream-processing
  40. Upstream manufacturing of gene therapy viral vectorsAvailable from: https://cellculturedish.com/upstream-manufacturing-gene-therapy-viral-vectors-2/
  41. Downstream manufacturing of gene therapy vectorsAvailable from: https://downstreamcolumn.com/downstream-manufacturing-gene-therapy-vectors-2/
  42. ValiantW.G. CaiK. ValloneP.M. A history of adventitious agent contamination and the current methods to detect and remove them from pharmaceutical products.Biologicals20228061710.1016/j.biologicals.2022.10.002 36347754
     [Google Scholar]
  43. PrusinerS.B. Biology and genetics of prions causing neuro-degeneration.Annu. Rev. Genet.201347160162310.1146/annurev‑genet‑110711‑155524 24274755
     [Google Scholar]
  44. KlugB. RobertsonJ.S. ConditR.C. Adventitious agents and live viral vectored vaccines: Considerations for archiving samples of biological materials for retrospective analysis.Vaccine201634516617662510.1016/j.vaccine.2016.02.015 27317264
     [Google Scholar]
  45. HarveyJ. FleetwoodA. OgilvieR. TeasdaleA. WilcoxP. SpanhaakS. Management of organic impurities in small molecule medicinal products: Deriving safe limits for use in early development.Regul. Toxicol. Pharmacol.20178411612310.1016/j.yrtph.2016.12.011 28038978
     [Google Scholar]
  46. PetriccianiJ. SheetsR. GriffithsE. KnezevicI. Adventitious agents in viral vaccines: Lessons learned from 4 case studies.Biologicals201442522323610.1016/j.biologicals.2014.07.003 25135887
     [Google Scholar]
  47. CMC activities for development of MAbs Contract PharmaAvailable from:https://www.contractpharma.com/issues/2010-04/view_features/cmc-activities-for-development-of-mabs/
  48. WilkieG.S. DicksonK.S. GrayN.K. Regulation of mRNA translation by 5′- and 3′-UTR-binding factors.Trends Biochem. Sci.200328418218810.1016/S0968‑0004(03)00051‑3 12713901
     [Google Scholar]
  49. FangZ. RajewskyN. The impact of miRNA target sites in coding sequences and in 3'UTRs.PLoS One201163e1806710.1371/journal.pone.0018067 21445367
     [Google Scholar]
  50. TenchovR. BirdR. CurtzeA.E. ZhouQ. Lipid nanoparticles—from liposomes to mRNA vaccine delivery, a landscape of research diversity and advancement.ACS Nano20211511169821701510.1021/acsnano.1c04996 34181394
     [Google Scholar]
  51. Evaluation of the quality, safety and efficacy of RNA-based2020
  52. ICH topic Q 5 D quality of biotechnological products: Derivation and characterisation of cell substrates used for production of biotechnological/biological products step 5 note for guidance on quality of biotechnological products: Derivation and characterisation of cell substrates used for production of biotechnological/biological products (CPMP/ICH/294/95)1998Available from: http://www.emea.eu.int
  53. Batch Culture - an overview ScienceDirect TopicsAvailable from: https://www.sciencedirect.com/topics/engineering/batch-culture [cited 2022 Dec 15].
  54. JunneS. NeubauerP. How scalable and suitable are single-use bioreactors?Curr. Opin. Biotechnol.20185324024710.1016/j.copbio.2018.04.003 29753977
     [Google Scholar]
  55. ICH topic Q 6 B specifications: Test procedures and acceptance criteria for biotechnological/biological products step 5 note for guidance on specifications: Test procedures and acceptance criteria for biotechnological/biological products.1999Available from: http://www.emea.eu.int
  56. Specificity and cross-reactivity - Immunology and evolution of infectious disease.NCBI BookshelfAvailable from: https://www.ncbi.nlm.nih.gov/books/NBK2396/
    [Google Scholar]
  57. UppoorR. Guidance for industry: CMC postapproval manufacturing changes to be documented in annual reports.2014Available from: www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
  58. StepCommittee for Human Medicinal Products ICH guideline Q9 on quality risk management2015Available from: www.ema.europa.eu/contact [cited 2023 May 16].
  59. CMC regulatory strategy.RAPSAvailable from: https://www.raps.org/news-and-articles/news-articles/2022/9/cmcregulatory-strategy
    [Google Scholar]
  60. What is a quality management system (QMS)? ASQAvailable from: https://asq.org/quality-resources/quality-management-system#Elements
  61. Pharmaceutical quality management system (QMS).SimplerQMSAvailable from: https://www.simplerqms.com/pharmaceuticalquality-management-system/
    [Google Scholar]
  62. VerchT. CampaC. ChéryC.C. Analytical quality by design, life cycle management, and method control.AAPS J.20222413410.1208/s12248‑022‑00685‑2 35149913
     [Google Scholar]
  63. Quality by design for monoclonal antibodies, Part 1: Establishing the foundations for process development BioProcess International-BioProcess InternationalAvailable from: https://bioprocessintl.com/analytical/upstream-development/quality-by-designfor-monoclonal-antibodies-part-1-establishing-the-foundations-forprocess-development/
  64. CberF. Approval letter HEPLISAV-B.2017Available from: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformati
    [Google Scholar]
  65. Biologicals G, Gould J. Our STN: BL 125614/0 BLA APPROVAL (b) (4) (b) (4) (b) (4) (b) (4).2017Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
  66. SangshettiJ.N. DeshpandeM. ZaheerZ. ShindeD.B. AroteR. Quality by design approach: Regulatory need.Arab. J. Chem.201710S3412S342510.1016/j.arabjc.2014.01.025
     [Google Scholar]
  67. KimE.J. KimJ.H. KimM.S. JeongS.H. ChoiD.H. Process analytical technology tools for monitoring pharmaceutical unit operations: A control strategy for continuous process verification.Pharmaceutics202113691910.3390/pharmaceutics13060919 34205797
     [Google Scholar]
  68. CasianT. NagyB. KovácsB. GalataD.L. HirschE. FarkasA. Challenges and opportunities of implementing data fusion in process analytical technology—A review.Molecules20222715484610.3390/molecules27154846 35956791
     [Google Scholar]
  69. N Politis SColombo P, Colombo G, M Rekkas D. Design of experiments (DoE) in pharmaceutical development.Drug Dev. Ind. Pharm.201743688990110.1080/03639045.2017.1291672 28166428
     [Google Scholar]
  70. ter HorstJ.P. TurimellaS.L. MetsersF. ZwiersA. Implementation of quality by design (QbD) principles in regulatory dossiers of medicinal products in the european union (EU) between 2014 and 2019.Ther. Innov. Regul. Sci.202155358359010.1007/s43441‑020‑00254‑9 33439461
     [Google Scholar]
  71. van de BergD. KisZ. BehmerC.F. Quality by design modelling to support rapid RNA vaccine production against emerging infectious diseases.NPJ Vaccines2021616510.1038/s41541‑021‑00322‑7 33927197
     [Google Scholar]
  72. LucianiF. GalluzzoS. GaggioliA. Implementing quality by design for biotech products: Are regulators on track?MAbs20157345145510.1080/19420862.2015.1023058 25853461
     [Google Scholar]
  73. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use pharmaceutical development Q8(R2).2009
  74. ICH topic Q 5 E comparability of biotechnological/biological products step 5 note for guidance on biotechnological/biological products subject to changes in their manufacturing process.2005Available from: http://www.emea.eu.int
  75. Eon-DuvalA. BrolyH. GleixnerR. Quality attributes of recombinant therapeutic proteins: An assessment of impact on safety and efficacy as part of a quality by design development approach.Biotechnol. Prog.201228360862210.1002/btpr.1548 22473974
     [Google Scholar]
  76. AlhakeemM.A. GhicaM.V. PîrvuC.D. AnuțaV. PopaL. Analytical quality by design with the lifecycle approach: A modern epitome for analytical method development.Acta Med. Marisiensis2019652374410.2478/amma‑2019‑0010
     [Google Scholar]
  77. Application Procedures INDIND application procedures: Clinical hold FDAAvailable from: https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-application-procedures-clinical-hold
  78. Disorders F on N and NS, Policy B on HS, Medicine I of. Drug development challenges.2014Available from: https://www.ncbi.nlm.nih.gov/books/NBK195047/
  79. Pfizer-BioNTech COVID-19 VaccinesFDAAvailable from: https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/pfizer-biontech-covid-19-vaccines
    [Google Scholar]
  80. Emergency use authorization (EUA) for an unapproved product review memorandum identifying information.
     [Google Scholar]
  81. Moderna COVID-19 VaccinesFDAAvailable from: https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/moderna-covid-19-vaccines
    [Google Scholar]
  82. KaslowD.C. KulinskiJ. Dvrpa /, Peterson R, Db O/, Dabrazhynetskaya A. Emergency Use Authorization (EUA) for an Unapproved Product Review Memorandum Identifying Information Application Type EUA Amendment Application Number EUA 27073, Amendment 622 Sponsor ModernaTX.
     [Google Scholar]
  83. Janssen COVID-19 VaccineFDAAvailable from: https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/janssen-covid-19-vaccine
    [Google Scholar]
  84. Novavax COVID-19 Vaccine, AdjuvantedFDAAvailable from: https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/novavax-covid-19-vaccine-adjuvanted
    [Google Scholar]
/content/journals/cdth/10.2174/0115748855267031240102070325
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CMC and QMS Regulatory Requirements and Challenges for mRNA-based Vaccines
Curr Drug Ther 20, 149 (2025); https://doi.org/10.2174/0115748855267031240102070325
/content/journals/cdth/10.2174/0115748855267031240102070325
/content/journals/cdth/10.2174/0115748855267031240102070325
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  • Article Type:     Review Article
Keyword(s): adventitious agents; Biologics; chemistry; controls; manufacturing; mRNA production; mRNA vaccine; quality; quality management system; vaccine

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