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Nondestructive Quantitative Inspection of Drug Products Using Benchtop NMR Relaxometry—the Case of NovoMix® 30

A Correction to this article was published on 06 June 2019

This article has been updated

Abstract

Batch-level inference-based quality control is the standard practice for drug products. However, rare drug product defects may be missed by batch-level statistical sampling, where a subset of vials in a batch is tested quantitatively but destructively. In 2013, a suspension insulin product, NovoLog® Mix 70/30 was recalled due to a manufacturing error, which resulted in insulin strength deviations up to 50% from the labeled value. This study analyzed currently marketed FlexPen® devices by the water proton transverse relaxation rate using a benchtop nuclear magnetic resonance relaxometer. The water proton transverse relaxation rate was found to be sensitive to detecting concentration changes of the FlexPen® product. These findings support the development of vial-level verification-based quality control for drug products where every vial in a batch is inspected quantitatively but nondestructively.

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Change history

  • 06 June 2019

    Typesetting error occurred and author corrections to the equations and text edits at the proofing stage were not incorporated in the published article. The original article has been corrected.

Abbreviations

NMR:

Nuclear magnetic resonance

T 2 :

Transverse relaxation time

R 2 :

Transverse relaxation rate

QC:

Quality control

DP:

Drug product

DS:

Drug substance

NS:

Number of scans

RD:

Relaxation delay

S/N:

Signal/noise

References

  1. U.S. Food and Drug Administration (FDA). MAUDE adverse event report: Novo Nordisk A/S Novopen insulin delivery device 2013. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/detail.cfm?mdrfoi__id=3621493. Accessed 09 Feb 2018.

  2. Ben Salem C, Fathallah N, Hmouda H, Bouraoui K. Drug-induced hypoglycaemia. Drug Saf. 2011;34:21–45. https://doi.org/10.2165/11538290-000000000-00000.

    CAS  Article  PubMed  Google Scholar 

  3. McCall AL. Insulin therapy and hypoglycemia. Endocrinol Metab Clin N Am. 2012;41:57–87. https://doi.org/10.1016/j.ecl.2012.03.001.

    Article  Google Scholar 

  4. European Medicines Agency (EMA). Batches of the insulin medicine NovoMix 30 FlexPen and Penfill to be recalled, (EMA/ 657469/ 2013). 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/10/WC500153147.pdf .Accessed 09 Feb 2018.

  5. Palmer E. Manufacturing glitch leaves novo insulin cartridges with bad fills. 2013.https://www.fiercepharma.com/supply-chain/manufacturing-glitch-leaves-novo-insulin-cartridges-bad-fills. Accessed 08 June 2018.

  6. USP 38-NF 33. Insulin Aspart Injection. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2015.

  7. Downing NS, Shah ND, Aminawung JA, Pease AM, Zeitoun JD, Krumholz HM, et al. Postmarket safety events among novel therapeutics approved by the US Food and Drug Administration between 2001 and 2010. JAMA. 2017;317:1854–63.

    Article  Google Scholar 

  8. Ebbers HC, NFd T, Hoefnagel MC, Nibbeling R, Mantel-Teeuwisse AK. Characteristics of product recalls of biopharmaceuticals and small-molecule drugs in the USA. Drug Discov Today. 2016;21:536–9. https://doi.org/10.1016/j.drudis.2015.10.020.

    Article  PubMed  Google Scholar 

  9. U.S. Food and Drug Administration (FDA). Recall (Biologics.https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Recalls/. Accessed 12 Oct 2018.

  10. Yu LX, Kopcha M. The future of pharmaceutical quality and the path to get there. Int J Pharm. 2017;528:354–9. https://doi.org/10.1016/j.ijpharm.2017.06.039.

    CAS  Article  PubMed  Google Scholar 

  11. Junker B, Kosinski M, Geer D, Mahajan R, Chartrain M, Meyer B, et al. Design-for-six-sigma for development of a bioprocess quality-by-design framework. PDA J Pharm Sci Technol. 2011;65:254–86. https://doi.org/10.5731/pdajpst.2011.00739.

    Article  PubMed  Google Scholar 

  12. Silva Elipe MV, Li L, Nagapudi K, Kook AM, Cobas C, Iglesias I, et al. Application of 19F time-domain NMR to measure content in fluorine-containing drug products. Magn Reson Chem. 2016;54:531–8. https://doi.org/10.1002/mrc.4223.

    CAS  Article  PubMed  Google Scholar 

  13. Corver J, Guthausen G, Kamlowski A. In-line non-contact check-weighing (NCCW) with nuclear magnetic resonance (NMR) presents new opportunities and challenges in process control. Pharm Eng. 2005;25:18–31.

    Google Scholar 

  14. NovoLog® Mix 70/30 (Insulin aspart protamine and insulin aspart injectable suspension) [package insert]. Plainsboro, NJ: NovoNordisk, Inc.; 2001.

  15. Meiboom S, Gill D. Modified spin-echo method for measuring nuclear relaxation times. Rev Sci Instrum. 1958;29:688–91. https://doi.org/10.1063/1.1716296.

    CAS  Article  Google Scholar 

  16. Yu YB, Feng Y, Taraban M. Water proton NMR for noninvasive chemical analysis and drug product inspection. Am Pharm Rev. 2017;20:34–8.

    CAS  Google Scholar 

  17. Mathonet S, Mahler H, Esswein ST, Mazaheri M, Cash PW, Wuchner K, et al. A biopharmaceutical industry perspective on the control of visible particles in biotechnology derived injectable drug products. PDA J Pharm Sci Technol. 2016;70:392–408. https://doi.org/10.5731/pdajpst.2015.006189.

    CAS  Article  PubMed  Google Scholar 

  18. Briggs KT, Taraban MB, Yu YB. Water proton NMR detection of amide hydrolysis and diglycine dimerization. Chem Commun. 2018;54:7003–6. https://doi.org/10.1039/C8CC03935F.

    CAS  Article  Google Scholar 

  19. Popel AS. Hydrodynamics of suspensions. Fluid Dyn. 1969;4:14–18. https://doi.org/10.1007/BF01094677.

    Article  Google Scholar 

  20. Butt H. Controlling the flow of suspensions. Science. 2011;331:868–9. https://doi.org/10.1126/science.1201543.

    CAS  Article  PubMed  Google Scholar 

  21. Shieu W, Lamar D, Stauch OB, Maa Y. Filling of high-concentration monoclonal antibody formulations: investigating underlying mechanisms that affect precision of low-volume fill by peristaltic pump. PDA J Pharm Sci Technol. 2016;70:143–56.

    CAS  Article  Google Scholar 

  22. Hanslip S, Desai KG, Palmer M, Bell S, Schofield P, Varma P, et al. Syringe filling of high-concentration mAb formulation: slow suck-back pump speed prevented filling needle clogging. J Pharm Sci. 2017;106:3651–3. https://doi.org/10.1016/j.xphs.2017.08.005.

    CAS  Article  PubMed  Google Scholar 

  23. Hanslip S, Desai KG, Palmer M, Kemp I, Bell S, Schofield P, et al. Syringe filling of a high-concentration mAb formulation: experimental, theoretical, and computational evaluation of filling process parameters that influence the propensity for filling needle clogging. J Pharm Sci. 2019;108:1130–8. https://doi.org/10.1016/j.xphs.2018.10.031.

    CAS  Article  PubMed  Google Scholar 

  24. Ventola CL. The drug shortage crisis in the United States: causes, impact, and management strategies. Pharm Ther. 2011;36:740–57.

    Google Scholar 

  25. Wilson E, Zhu C, Galea S, Marko A, Victoria Urdaneta V, Straus W. Turning up the heat: effect of new vaccine for children’s (VFC) program recommendations for use of temperature monitors upon incorrect product storage adverse event reporting. Vaccine. 2018;36:1516–20. https://doi.org/10.1016/j.vaccine.2017.10.059.

    Article  PubMed  Google Scholar 

  26. Rosenberg AS, Verthelyi D, Cherney BW. Managing uncertainty: a perspective on risk pertaining to product quality attributes as they bear on immunogenicity of therapeutic proteins. J Pharm Sci. 2012;101:3560–7. https://doi.org/10.1002/jps.23244.

    CAS  Article  PubMed  Google Scholar 

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Funding Source

K.T.B. received an M-CERSI Postdoctoral Fellowship from the FDA. A part of the work was supported by the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL). The University of Maryland Baltimore provided additional funding.

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Authors

Corresponding author

Correspondence to Y. Bruce Yu.

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Conflict of Interest

K.T. Briggs, M.B. Taraban, and Y.B. Yu are co-inventors on issued and pending patents on wNMR technologies.

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This article does not contain any studies with human or animal subjects.

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Key Points

• Low-field benchtop NMR relaxometry is capable to detect drug dose deviations in intact drug products by measuring the water proton transverse relaxation rate.

• Measuring the water proton relaxation rate of a drug product is a nondestructive method that has the potential to serve as a quality control method for released drug products.

• Prime candidates for nondestructive verification-based quality control are scenarios where the occurrence of drug product defects is low, but the consequences of a defect are serious.

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Briggs, K.T., Taraban, M.B., Wang, W. et al. Nondestructive Quantitative Inspection of Drug Products Using Benchtop NMR Relaxometry—the Case of NovoMix® 30. AAPS PharmSciTech 20, 189 (2019). https://doi.org/10.1208/s12249-019-1405-0

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  • DOI: https://doi.org/10.1208/s12249-019-1405-0

KEY WORDS

  • NMR
  • insulin
  • quality control
  • nondestructive inspection
  • adverse events