The Pharmaceutical Development of rhDNase (Dornase Alpha) for the Treatment of Cystic Fibrosis

Chapter
First Online:

Abstract

This review summarizes the development of rhDNase as a pharmaceutical for pulmonary delivery including development and stability assessment of a formulation, compatibility with jet nebulization, characterization of the aerosols produced by jet nebulization, and compatibility and storage stability of the final drug product configuration in blow-fill seal plastic ampoules. These evaluations supported the eventual health authority registration under the brand name Pulmozyme®. More recent life-cycle development efforts have involved performing in vitro technical feasibility studies to determine whether the existing drug product formulation of Pulmozyme® can be delivered by a portable electronic mesh nebulizer without any impact on the molecular, chemical, and physical attributes of product quality and with similar dosage as those originally used to register the drug. These studies illustrate the complexity of combination product development and life-cycle management to maintain the modernity of product delivery systems.

Keywords

Pulmozyme Dornase alpha rhDNase Combination product life-cycle management Nebulizer product quality impact 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Boat T, Welsh MJ, Beaudet A, Cystic Fibrosis. In: Scriver C, et al., editor. The metabolic basis of inherited disease. New York: McGraw Hill;1989. pp. 2649–2860.Google Scholar
  2. 2.
    MacDonald KD, McKenzie KR, Zeitlin PL. Cystic fibrosis transmembrane regulator protein mutations: ‘class’ opportunity for novel drug innovation. Paediatr. Drugs. 2007;9(1):1–10.PubMedCrossRefGoogle Scholar
  3. 3.
    Tsui LC, Buchwald M. Biochemical and molecular genetics of cystic fibrosis. Adv Hum Genet. 1991;20:153–266.PubMedCrossRefGoogle Scholar
  4. 4.
    Abeliovich D, Lavon IP, Lerer I, Cohen T, Springer C, Avital A, Cutting G. Screening for five mutations detects 97 % of cystic fibrosis (cf) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population. Am J Hum Genet. 1992;51:951–6.PubMedCentralPubMedGoogle Scholar
  5. 5.
    Chernick WS, Barbero GJ. Composition of tracheobronchial secretions in cystic fibrosis of the pancreas and bronchiectasis. Pediatrics. 1959;24:739–45.PubMedGoogle Scholar
  6. 6.
    Potter JL, Matthews LW, Lemm J, Spector S. Human pulmonary secretions in health and disease. Ann N Y Acad Sci. 1963;106:692–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Armstrong JB, White JC. Liquefaction of viscous purulent exudates by deoxyribonuclease. Lancet. 1950:739–40.Google Scholar
  8. 8.
    Chernick WS, Barbero GJ, Eichel HJ. In-vitro evaluation of effect of enzymes on tracheobronchial secretions from patients with cystic fibrosis. Pediatrics. 1961;27:589–96.PubMedGoogle Scholar
  9. 9.
    Elmes PC, White JC. Deoxyribonuclease in the treatment of purulent bronchitis. Thorax. 1953;8:295–300.PubMedCrossRefGoogle Scholar
  10. 10.
    Salomon A, Herchfus JA, Segal MS. Aerosols of pancreatic dornase in bronchopulmonary disease. Anna Allergy. 1954;12:71–9.Google Scholar
  11. 11.
    Spier R, Witebsky E, Paine JR. Aerosolized pancreatic dornase and antibiotics in pulmonary infections. JAMA. 1961;178:878–86.PubMedCrossRefGoogle Scholar
  12. 12.
    Lieberman J. Enzymatic dissolution of pulmonary secretions. Am J Dis Chil. 1962;104:342–8.CrossRefGoogle Scholar
  13. 13.
    Raskin P. Bronchospasm after inhalation of pancreatic dornase. Am Rev Respir Dis. 1968;98:597–8.Google Scholar
  14. 14.
    Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL. Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci U S A. 1990;87(23):9188–92.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Aitken ML. Clinical trials of recombinant human DNase in cystic fibrosis patients. Monaldi Arch Chest Dis. 1993;48(6):653–6.PubMedGoogle Scholar
  16. 16.
    Hubbard RC, McElvaney NG, Birrer P, Shak S, Robinson WW, Jolley C, Wu M, Chernick MS, Crystal RG. A preliminary study of aerosolized recombinant human deoxyribonuclease I in the treatment of cystic fibrosis. N Engl J Med. 1992;326(12):812–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Ramsey BW, Astley SJ, Aitken ML, Burke W, Colin AA, Dorkin HL, Eisenberg JD, Gibson RL, Harwood IR, Schidlow DV, et al. Efficacy and safety of short-term administration of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis. Am Rev Respir Dis. 1993;148(1):145–51.PubMedCrossRefGoogle Scholar
  18. 18.
    Ranasinha C, Assoufi B, Shak S, Christiansen D, Fuchs H, Empey D, Geddes D, Hodson M. Efficacy and safety of short-term administration of aerosolised recombinant human DNase I in adults with stable stage cystic fibrosis. Lancet. 1993;342(8865):199–202.PubMedCrossRefGoogle Scholar
  19. 19.
    Pressler T. Review of recombinant human deoxyribonuclease (rhDNase) in the management of patients with cystic fibrosis. Biologics. 2008;2(4):611–7.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Cacia J, Quan CP, Vasser M, Sliwkowski MB, Frenz J. Protein sorting by high-performance liquid chromatography. I. Biomimetic interaction chromatography of recombinant human deoxyribonuclease I on polyionic stationary phases. J Chromatogr. 1993;634(2):229–39.PubMedCrossRefGoogle Scholar
  21. 21.
    Cleland JL, Powell MF, Shire SJ. The development of stable protein formulations: a close look at protein aggregation, deamidation and oxidation. Crit Rev Ther Drug Carrier Syst. 1993;10(4):307–77.PubMedGoogle Scholar
  22. 22.
    Wright HT. Deamidation of asparaginyl and glutaminyl residues in proteins. CRC Crit Rev Biochem Mol Biol. 1991;26:1–52.CrossRefGoogle Scholar
  23. 23.
    Balmes JR, Fine JM, Christian D, Gordon T, Sheppard D. Acidity potentiates bronchoconstriction induced by hypoosmolar aerosols. Am Rev Respir Dis. 1988;138:35–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Beasley R, Rafferty P, Holgate ST. Adverse reactions to the non-drug constituents of nebulizer solutions. Br J Clin Pharmac. 1988;25:283–7.CrossRefGoogle Scholar
  25. 25.
    Desager KN, Van Bever HP, Stevens WJ. Osmolality and pH of antiasthmatic drug solutions. Agents Actions. 1990;31:225–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Fine JM, Gordon T, Thompson JE, Sheppard D. The role of titratable acidity in acid aerosol-induced bronchoconstriction. Am Rev Respir Dis. 1987;135:826–30.PubMedGoogle Scholar
  27. 27.
    Sant’Ambrogio G, Anderson JW, Sant’Ambrogio FB, Mathew OP. Response to laryngeal receptors to water solutions of different osmolality and ionic composition. Respir Med. 1991;85(Supplement A):57–60.PubMedCrossRefGoogle Scholar
  28. 28.
    Snell NJC. Adverse reactions to inhaled drugs. Respir Med. 1990;84:345–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Gonda I, Kayes JB, Groom CV, Fildes FJT. Characterization of hygroscopic inhalation aerosols. In: Stanley-Wood NG, editor. Particle size analysis. New York: Wiley; 1982. pp. 31–43.Google Scholar
  30. 30.
    Gonda I, Phipps PR. Some consequences of instability of aqueous aerosols produced by jet and ultrasonic nebulizers. In: Masuda S, Takahashi K, editor. Aerosols. Vol. 1. New York: Pergamon Press; 1991. pp. 227–30.Google Scholar
  31. 31.
    Godden DJ, Borland C, Lowry R, Higenbottam TW. Chemical specificity of coughing in man. Clin Sci. 1986;70:301–06.PubMedGoogle Scholar
  32. 32.
    Cipolla D, Gonda I, Meserve K, Weck S, Shire SJ. Formulation and aerosol delivery of recombinant deoxyribonucleic acid derived human deoxyribonuclease I. In: Cleland JL, Langer R, editor. ACS Symposium Series 567, formulation and delivery of proteins and peptides. Washington: American Chemical Society; 1994. pp. 322–42.Google Scholar
  33. 33.
    Poulos TL, Price PA. Some effects of calcium ions on the structure of bovine pancreatic deoxyribonuclease A. J Biol Chem. 1972;247:2900–4.PubMedGoogle Scholar
  34. 34.
    Shire SJ. Stability characterization and formulation development of recombinant human deoxyribonuclease I [Pulmozyme®, (Dornase Alpha)]. In: Pearlman R, Wang YJ, editor. Formulation, characterization and stability of protein drugs. New York: Plenum; 1996. pp. 393–426.Google Scholar
  35. 35.
    Wiberg JS. On the mechanism of metal activation of deoxyribonuclease I. Arch Biochem Biophys. 1958;73:337–58.PubMedCrossRefGoogle Scholar
  36. 36.
    Price PA. Characterization of Ca++ and Mg++ binding to bovine pancreatic deoxyribonuclease A. J Biol Chem. 1972;247:2895–9.PubMedGoogle Scholar
  37. 37.
    Capasso S, Mazzarella L, Zagari A. Deamidation via cyclic imide of asparaginyl peptides: Dependence on salts, buffers and organic solvents. Pept Res. 1991;4(4):234–8.PubMedGoogle Scholar
  38. 38.
    Meserve K, Weck S, Shire SJ. Stability of recombinant deoxyribonuclease I (rhDNase) in plastic vials manufactured by the automatic liquid packaging (ALP) system. Pharm Res. 1994;11(10):S–74.Google Scholar
  39. 39.
    Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8(3):E501–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Wang W, Singh SK, Li N, Toler MR, King KR, Nema S. Immunogenicity of protein aggregates—concerns and realities. Int J Pharm. 2012;431(1–2):1–11.PubMedGoogle Scholar
  41. 41.
    Kumar S, Singh SK, Wang X, Rup B, Gill D. Coupling of aggregation and immunogenicity in biotherapeutics: T- and B-cell immune epitopes may contain aggregation-prone regions. Pharm Res. 2011;28(5):949–61.PubMedCrossRefGoogle Scholar
  42. 42.
    Cipolla D, Gonda I, Shire SJ. Characterization of aerosols of human recombinant deoxyribonuclease I (rhDNase) generated by jet nebulizers. Pharm Res. 1994;11(4):491–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Cipolla DC, Clark AR, Chan H-K, Gonda I, Shire SJ. Assessment of aerosol delivery systems for recombinant human deoxyribonuclease. STP Pharma Sci. 1994;4(1):50–62.Google Scholar
  44. 44.
    Geller DE, Eigen H, Fiel SB, Clark A, Lamarre AP, Johnson CA, Konstan MW. Effect of smaller droplet size of dornase alfa on lung function in mild cystic fibrosis. Pediatr Pulmonol. 1998;25(2):83–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Byron PR. Aerosol formulation, generation, and delivery using nonmetered systems. In: Byron PR, editor. Respiratory drug delivery. Vol. Chapter 6, CRC Press; 1990. pp. 143–65.Google Scholar
  46. 46.
    Geller DE. New liquid aerosol generation devices: systems that force pressurized liquids through nozzles. Resp Care. 2002;47(12):1392–404; discussion 1404–1395.Google Scholar
  47. 47.
    Knoch M, Keller M. The customised electronic nebuliser: a new category of liquid aerosol drug delivery systems. Expert Opin Drug Deliv. 2005;2(2):377–90.PubMedCrossRefGoogle Scholar
  48. 48.
    Naehrig S, Lang S. Lung function in adult patients with cystic fibrosis after using the eFlow® rapid for one year. Eur J Med Res. 2011;16(2):63–6.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Vecellio L. The mesh nebulizer: a recent technical innovation for aerosol delivery. Breathe. 2006;2(3):253–60.Google Scholar
  50. 50.
    Scherer T, Geller DE, Owyang L, Tservistas M, Keller M, Boden N, Kesser KC, Shire SJ. A technical feasibility study of dornase alfa delivery with eFlow (R) vibrating membrane nebulizers: aerosol characteristics and physicochemical stability. J Pharm Sci. 2011;100(1):98–109.PubMedCrossRefGoogle Scholar
  51. 51.
    Clark AR. The use of laser diffraction for the evaluation of the aerosol clouds generated by medical nebulizers. Int J Pharm. 1995;115(1):69–78.CrossRefGoogle Scholar
  52. 52.
    Keller M, Tservistas M, Bucholski A, Hug M, Knoch M. Correlation of laser diffraction and cascade impaction data for aqueous solutions aerosolized by the eFlow® electronic nebulizer. Proc Respir Drug Deliv. 2006:745–748.Google Scholar
  53. 53.
    Johnson JC, Waldrep JC, Guo J, Dhand R. Aerosol delivery of recombinant human DNase I: in vitro comparison of a vibrating-mesh nebulizer with a jet nebulizer. Respir Care. 2008;53(12):1703–8.PubMedGoogle Scholar
  54. 54.
    Potter RW, Hurren TJ, Nickerson C, Hatley RH. Comparison of the delivery characteristics of dornase alpha from the I-NEB1 AAD® system and the Sidestream® jet nebulizer. Pediatic Pulm Supp. 2008;31:483.Google Scholar
  55. 55.
    Standaert TA, Morlin GL, Williams-Warren J, Joy P, Pepe MS, Weber A, Ramsey BW. Effects of repetitive use and cleaning techniques of disposable jet nebulizers on aerosol generation. Chest. 1998;114(2):577–86.PubMedCrossRefGoogle Scholar
  56. 56.
    Rottier BL, van Erp CJP, Sluyter TS, Heijerman HGM, Frijlink HW, de Boer AH. Changes in performance of the pari eFlow (R) rapid and pari LC Plus™ during 6 months use by CF patients. J Aerosol Med Pulm D. 2009;22(3):263–9.CrossRefGoogle Scholar
  57. 57.
    Geller DE, Kesser KC. Guidance on the use of eFlow nebulizers (Altera® and Trio®). 2010.Google Scholar
  58. 58.
    Maa YF, Nguyen PA, Andya JD, Dasovich N, Sweeney TD, Shire SJ, Hsu CC. Effect of spray drying and subsequent processing conditions on residual moisture content and physical/biochemical stability of protein inhalation powders. Pharm Res. 1998;15(5):768–75.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Genentech, Late Stage Pharmaceutical DevelopmentSan FranciscoUSA

Personalised recommendations