Advertisement

Contemporary Approaches to Development and Manufacturing of Lyophilized Parenterals

  • Edward H. Trappler
Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 6)

Abstract

This chapter provides a historical reference, covers the progression in the scientific and technological development, highlights the contemporary aspects, and describes the application of the current USFDA guidance to the development through commercial life cycle for lyophilized products. Considerations of designing formulations, including the use of organic solvents, and influence of packaging are noted. Emphasis is placed on the engineering of the lyophilization process, establishing the critical process parameters, and defining of the critical quality attributes. Utility of applying the US FDA process analytical technology initiative, as well as the notion of applying design space principles to the lyophilization process is included, leading into discussions on applying the current USFDA guideline on process validation to the development and manufacturing. Current challenges and unique aspects in development of lyophilized products are also highlighted, including poorly soluble drug substances, novel delivery systems, improving manufacturing capabilities, and reducing unit costs for world wide product distribution. This presentation encompasses the progression of the technological developments, reviews current thinking on the science and technology, and highlights contemporary approaches to the development and manufacturing of lyophilized parenterals.

Keywords

Chamber Pressure Product Temperature Residual Moisture Lyophilization Process Shelf Temperature 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Bosch AM, Shultz CA (2008) Freeze drying of pharmaceuticals and biologicals conference, Breckenridge, COGoogle Scholar
  2. Bursac R, Sever R, Hunek B (2009) A practical method for resolving the nucleation problem in lyophilization. Bio Process Int 7:66–72Google Scholar
  3. Byron PR, DeLuca PP, Twonsend MW (1990) The effects of formulation additives on the degradation of freeze dried ribonuclease A. Pharm Res 7:1086–1091PubMedCrossRefGoogle Scholar
  4. Cannon TC, Shemeley KA (2004) Statistical evaluation of vial design features that influence sublimation rates during primary drying. Pharm Res 21:536–542PubMedCrossRefGoogle Scholar
  5. Cannon TC, Trappler EH (2000) Influence of lyophilization on the polymorphic behavior of mannitol. PDA J Pharm Sci Technol 54(1):13–22PubMedGoogle Scholar
  6. Chapman K (1984) The PAR approach to process validation. Pharm Technol 4:47–54Google Scholar
  7. DeLuca PP, Kasrain K (1995) The effect of tertiary butyl alcohol on the resistance of the dry product layer during primary drying. Pharm Res 12:491–495PubMedCrossRefGoogle Scholar
  8. Deluca P, Lachman L (1965) Lyophilization of pharmaceuticals. I: Effects of certain physical-chemical properties. J Pharm Sci 54:617–624PubMedCrossRefGoogle Scholar
  9. Evans SA, Morris KR, MacKenzie AP, Lordi NG (1995) Dielectric characterization of thermodynamic first order events in model frozen systems intended for lyophilization. PDA J Pharm Sci Technol 49:1–8Google Scholar
  10. Fang WJ, Qi W, Prestrelski S, Carpenter JF (2012) Effects of excipients on the chemical and physical stability of glucagon during freeze-drying and storage in dried formulations. Pharm Res 29:3278–3291PubMedCrossRefGoogle Scholar
  11. Fitzpartick S, Saklatvala R (2003) Understanding the physical stability of freeze-dried dosage form from the glass transition temperature of the amorphous components. J Pharm Sci 92:2504–2510Google Scholar
  12. Flamberg DE, Francis DL, Morgan SL, Wicks GF (1970) Low temperature vacuum drying of sterile parenterals from ethanol. Bull Parenter Drug Assoc 24:210–217Google Scholar
  13. Food and Drug Administration (1993) Guide to Inspection of Lyophilization of Parenterals, FDA, July 1993 http://ww.fda.gov/ICECI/Inspections/InspectionGuides /ucm074909.htm
  14. Food and Drug Administration (2011) Guidance for Industry Process Validation: General Principles and Practices, FDA, January 2011. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryinformation/Guidances/default.htm
  15. Gieseler H, Kessler W, Finson M, Davis S, Mulhall P, Bons V, Debo D, Pikal MJ (2007) Evaluation of tunable diode laser absorption spectroscopy for in-process water vapor mass flux measurements during freeze drying. J Pharm Sci 96:1776–1793PubMedCrossRefGoogle Scholar
  16. Ginnette LF, Graham RP, Morgan AI (1958) Freeze drying rates. In: Vacuum symposium transactions, fifth national symposium on vacuum technology transitions, Pergamon Press, NYGoogle Scholar
  17. Hora MS, Wolfe SN (2004) Critical steps in the preparation of elastomeric closures for biopharmaceutical freeze dried products. Marcel Dekker, New YorkGoogle Scholar
  18. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (2009) Pharmaceutical development Q8(R2)Google Scholar
  19. Johnson R, Muhvich K, Tidswell E, Trappler EH (2012) Current sterile and lyo is discussed at joint IG session. PDA Letter XLVIII:3847. Parenteral Drug Association, Bethesda, MD www.pda.org/pdaletter
  20. Kaifman S, Novara M, Potter C, Sadowski P (2012) Self-administration of injectables. BioPharm Int 4:42–48Google Scholar
  21. Konstantinidis AK, Kuu W, Otten L, Nail SL, Sever RR (2011) Controlled nucleation in freeze-drying: effect on pore size in the dried product layer, mass transfer resistance, and primary drying rate. J Pharm Sci 100(8):3453–3470. doi: 10.1002/jps.22561 PubMedCrossRefGoogle Scholar
  22. Korey DJ, Schwartz JB (1989) Effects of excipients on the crystallization of pharmaceutical compounds during lyophilization. J Parenter Sci Technol 43:80–83PubMedGoogle Scholar
  23. Landsberg (1956), Proceedings, Vacuum Symposium Transactions, Continuous Analysis of Gasses in a High Vacuum Furnace with a Monitoring Mass Spectrometer, Committee on Vacuum Techniques, American Vacuum Society, BostonGoogle Scholar
  24. Milton N, Pikal MJ, Roy ML, Nail SL (1997) Evaluation of manometric temperature measurement as a method on monitoring product temperature during lyophilization. PDA J Pharm Sci Technol 51:7–16PubMedGoogle Scholar
  25. Nail S (1980) Effect of chamber pressure on heat transfer in the freeze drying of parenteral solutions. J Parenter Sci Technol 5:358–368Google Scholar
  26. Nail SL, Johnson W (1991) Methodology for in-process determination of residual water in freeze-dried products. Dev Boil Stand 44:137–151Google Scholar
  27. Patel SM, Bhugra C, Pikal MJ (2009) Reduced pressure ice fog technique for controlled ice nucleation during freeze-drying. AAPS PharmSciTech 10:1406–1411PubMedCrossRefGoogle Scholar
  28. Pikal MJ, Roy ML (1989) Process control in freeze drying: determination of the end point of sublimation drying by an electronic moisture sensor. J Parenter Sci Technol 44:60–66Google Scholar
  29. Pikal MJ, Shah S, Senior D, Lang JE (1983) Physical chemistry of freeze-drying: measurement of sublimation rates for frozen aqueous solutions by a microbalance technique. J Pharm Sci 72:635–650PubMedCrossRefGoogle Scholar
  30. Pikal MJ, Roy ML, Shah S (1984) Mass and heat transfer in vial freeze drying of pharmaceuticals: role of the vial. J Pharm Sci 73:1224–1237PubMedCrossRefGoogle Scholar
  31. Pikal MJ, Shah S, Roy ML, Putman R (1990) The secondary drying stage of freeze drying: drying kinetics as a function of temperature and chamber pressure. Int J Pharm 60:203–217CrossRefGoogle Scholar
  32. Seager H, Taskis M, Syrop M, Lee TJ (1985) Structure of products prepared by freeze-drying solutions containing organic solvents. J Parenter Sci Technol 39:161–179PubMedGoogle Scholar
  33. Searles JA, Carpenter JF, Randolph TW (2001) Annealing to optimize the primary drying rate, reduce freeze-induced drying rate heterogeneity, and determine Tg’ in pharmaceutical lyophilization. J Pharm Sci 90:872–887PubMedCrossRefGoogle Scholar
  34. Stark J (1998) Blood. Pretence-Hall, New YorkGoogle Scholar
  35. Teagarden DL, Baker DS (2002) Practical aspects of lyophilization using non-aqueous co-solvent systems. J Pharm Sci 15:115–133Google Scholar
  36. Trappler EH (2004) Validation of lyophilization: equipment and process. In: Constantino H, Pikal MJ (eds) Lyophilization of biopharmaceuticals. AAPS Press, Arlington, VAGoogle Scholar
  37. Trappler (2011) Proceedings, International Society of Lyophilization – Freeze Drying Midwest Chapter Annual Meeting, April, 2011Google Scholar
  38. Trappler EH, Mutchler AM, Day LA (2012) Effect of vial construction on performance and product temperature during freezing and freeze drying. In: Freeze drying of pharmaceuticals and biologicals conference, Breckenridge, COGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2013

Authors and Affiliations

  1. 1.Lyophilization Technology, Inc.IvylandUSA

Personalised recommendations