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Lyophilization (freeze-drying)

Lyophilization, also called freeze-drying, is a process that removes water from a frozen material by sublimation and then desorption. An FDA inspection guide describes it as three separate, unique and interdependent processes: freezing, primary drying (sublimation) and secondary drying (desorption).[1]

What happens in each stage?

A review by Tang and Pikal discusses control of ice nucleation and crystallization during freezing and how freezing affects the rest of the process and the final product.[2]

In primary drying, ice is removed by sublimation. In secondary drying, remaining water is removed by desorption.[1]

How is a freeze-drying process designed?

Tang and Pikal write that the design of freeze-drying processes is often approached by trial and error, and that commercial processes are consequently often neither robust nor efficient. Their thesis is that designing an optimized process is not particularly difficult for most products if simple rules based on well-accepted scientific principles are followed.[2]

Which temperatures limit the process?

Tang and Pikal discuss the collapse temperature and the thermal transition denoted Tg′, and give procedures for selecting a target product temperature for primary drying.[2]

The FDA inspection guide states that the product temperature should be held at least 4-5° below the eutectic point.[1]

Which settings control the product temperature?

Tang and Pikal give guidelines for selecting the shelf temperature and chamber pressure needed to reach the target product temperature without thermal or mass transfer overload of the freeze dryer, and separate guidelines for secondary drying.[2]

What does freeze-drying design consider for proteins?

The review by Tang and Pikal gives general advice on common stability issues with proteins in freeze-drying process design.[2]

ICH Q6B lists moisture content for lyophilized drug products among typical pharmacopoeial tests, reflecting that residual water is a measured attribute of a freeze-dried material.[3]

ICH Q6B defines degradation products as molecular variants resulting from changes in the desired product over time or by the action of, for example, light, temperature, pH or water. For synthetic peptides, D'Hondt and colleagues list degradation mechanisms including beta-elimination, diketopiperazine, pyroglutamate and succinimide formation.[3],[4]

ICH Q7 defines an expiry date as the date during which a material is expected to remain within established shelf life specifications if stored under defined conditions, and a retest date as the date when a material should be re-examined to ensure that it is still suitable for use.[5]

Limitations

Lyophilization is a drying process. ICH Q6B lists moisture content for lyophilized products as a test in its own right; identity, purity and endotoxin are measured by separate tests.[1],[3]

Tang and Pikal give general advice on common stability issues with proteins and state that unusual and difficult stability issues are beyond the scope of their review.[2]

The appearance of a dried cake does not by itself show that the process stayed below the collapse temperature or that residual water is within a limit.[2],[3]

This page describes the process in general terms. It is not a description of how any PepGenex material was produced, and it contains no preparation or handling instructions.

This page describes what the cited documents say. It is not a statement that any PepGenex material has been manufactured, tested or released under any of them.

Compound profiles

Research peptide profiles in this library. What this page describes applies to peptide lots in general; none of these profiles reports a result of it for any lot.

References

  1. U.S. FDA. Guide to Inspections: Lyophilization of Parenteral (7/93). FDA Inspection Guide, July 1993
  2. Tang X, Pikal MJ. Design of freeze-drying processes for pharmaceuticals: practical advice. Pharm Res. 2004;21(2):191-200. PMID 15032301 · DOI 10.1023/B:PHAM.0000016234.73023.75
  3. ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. U.S. FDA guidance for industry, August 1999. FDA docket FDA-1998-D-0003
  4. D'Hondt M, Bracke N, Taevernier L, et al. Related impurities in peptide medicines. J Pharm Biomed Anal. 2014;101:2-30. PMID 25044089 · DOI 10.1016/j.jpba.2014.06.012
  5. ICH Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients. U.S. FDA guidance for industry, September 2016. FDA docket FDA-1995-D-0288