Lyophilisation: difference between revisions

Diff·revision 12 → 13·23:19, 13 Jan 2025

Difference between revision 12 and revision 13 of Lyophilisation. 13 lines changed; the page grew by 1,940 bytes.

Revision 12 — 04:03, 28 Dec 2024 SupplyWatchSuri (talk) add the collapse-temperature point, sourced 13,494 bytes +1,164	Revision 13 — 23:19, 13 Jan 2025 OpenLabelOtto (talk) sentence case in headings per PP:MOS 15,434 bytes +1,940
13	\| Product temperature, primary drying = −40 to −20 °C	13	\| Product temperature, primary drying = −40 to −20 °C
14	\| Shelf temperature, secondary drying = 20–40 °C	14	\| Shelf temperature, secondary drying = 20–40 °C
+		15	<!-- Quality attributes -->
+		16	\| Residual moisture, usual target = below 3% w/w
+		17	\| Determined by = [[Karl Fischer titration]] or [[Loss on drying\|loss on drying]]
+		18	\| Principal cake defect = Collapse above the collapse temperature
+		19	\| Reconstitution time, usual expectation = under 1 minute for a small peptide
15	}}	20	}}
16	{{hatnote\|For the reverse operation performed by the end user, see [[Reconstitution of lyophilised peptides]]. For measurement of the water that remains, see [[Karl Fischer titration]].}}	21	{{hatnote\|For the reverse operation performed by the end user, see [[Reconstitution of lyophilised peptides]]. For measurement of the water that remains, see [[Karl Fischer titration]].}}
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82	A 2.0 mL fill therefore requires approximately 12.5 hours of primary drying under these conditions, before any safety margin is added. Doubling the shelf-to-product temperature difference halves that figure, which is why the choice of critical temperature — and how close the cycle is permitted to approach it — dominates cycle economics.{{r\|tang2004,rambhatla2003}}	87	A 2.0 mL fill therefore requires approximately 12.5 hours of primary drying under these conditions, before any safety margin is added. Doubling the shelf-to-product temperature difference halves that figure, which is why the choice of critical temperature — and how close the cycle is permitted to approach it — dominates cycle economics.{{r\|tang2004,rambhatla2003}}
83		88
+		89	Vials do not all behave alike. Those at the edge of a shelf receive additional radiant heat from chamber walls and door, sublime faster, and reach higher product temperatures; this edge-vial effect can amount to several degrees and is the usual reason a cycle validated on a laboratory dryer fails at production scale.{{r\|rambhatla2003}}
+		90
84	=== Collapse and eutectic melting ===	91	=== Collapse and eutectic melting ===
85	Two distinct structural failures bound primary drying. In a system whose freeze-concentrate crystallises, exceeding the eutectic melting temperature produces liquid, and the vial dries as a shrunken residue or a glassy shell — usually described on inspection as melt-back. In an amorphous system, exceeding a temperature a few degrees above Tg′ allows viscous flow of the freeze-concentrated matrix into the pores that the sublimed ice has vacated. The dried layer loses its structure, and the result is a shrunken, sometimes glassy or foamed cake. The temperature at which this becomes observable by freeze-drying microscopy is the collapse temperature, Tc, conventionally 1–3 °C above Tg′ for small-molecule and peptide systems.{{r\|tang2004}}	92	Two distinct structural failures bound primary drying. In a system whose freeze-concentrate crystallises, exceeding the eutectic melting temperature produces liquid, and the vial dries as a shrunken residue or a glassy shell — usually described on inspection as melt-back. In an amorphous system, exceeding a temperature a few degrees above Tg′ allows viscous flow of the freeze-concentrated matrix into the pores that the sublimed ice has vacated. The dried layer loses its structure, and the result is a shrunken, sometimes glassy or foamed cake. The temperature at which this becomes observable by freeze-drying microscopy is the collapse temperature, Tc, conventionally 1–3 °C above Tg′ for small-molecule and peptide systems.{{r\|tang2004}}
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89	Conservative practice therefore sets the target product temperature 2–5 °C below Tc and accepts the longer cycle. Aggressive cycles that run within a degree of Tc exist and are defensible when the critical temperature has been measured for the specific formulation rather than assumed from a table.{{r\|tang2004}}	96	Conservative practice therefore sets the target product temperature 2–5 °C below Tc and accepts the longer cycle. Aggressive cycles that run within a degree of Tc exist and are defensible when the critical temperature has been measured for the specific formulation rather than assumed from a table.{{r\|tang2004}}
90		97
+		98	=== Endpoint determination ===
+		99	Primary drying ends when the last ice sublimes, and the transition is detectable because the vapour load on the condenser falls. Several signals are used. Comparative pressure measurement exploits the difference between a capacitance manometer, which reads total pressure, and a Pirani gauge, whose calibration depends on gas composition: as water vapour is replaced by nitrogen, the Pirani reading converges on the manometer reading, and the convergence marks the endpoint. Pressure-rise testing isolates the chamber briefly and measures the rate at which pressure recovers. Product thermocouples show a rise toward shelf temperature once no ice remains to consume heat, though a thermocouple perturbs nucleation in the vial it occupies and reads that vial rather than the batch.{{r\|patel2010}}
+		100
+		101	The practical difficulty is that the last vials to finish are not the ones being monitored. Endpoint criteria are therefore normally applied with a hold period appended, and the batch is held under primary-drying conditions for a defined time after the signal is observed.{{r\|patel2010}}
+		102
91	== References ==	103	== References ==
92	{{reflist}}	104	{{reflist}}
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98	<ref name="kasper2011">Kasper JC, Friess W. "The freezing step in lyophilization: physico-chemical fundamentals, freezing methods and consequences on process performance and quality attributes of biopharmaceuticals." ''European Journal of Pharmaceutics and Biopharmaceutics'' 78(2):248–263 (2011).</ref>	110	<ref name="kasper2011">Kasper JC, Friess W. "The freezing step in lyophilization: physico-chemical fundamentals, freezing methods and consequences on process performance and quality attributes of biopharmaceuticals." ''European Journal of Pharmaceutics and Biopharmaceutics'' 78(2):248–263 (2011).</ref>
99	<ref name="rambhatla2003">Rambhatla S, Pikal MJ. "Heat and mass transfer scale-up issues during freeze-drying, I: atypical radiation and the edge vial effect." ''AAPS PharmSci'' 5(2):article 14 (2003).</ref>	111	<ref name="rambhatla2003">Rambhatla S, Pikal MJ. "Heat and mass transfer scale-up issues during freeze-drying, I: atypical radiation and the edge vial effect." ''AAPS PharmSci'' 5(2):article 14 (2003).</ref>
+		112	<ref name="patel2010">Patel SM, Doen T, Pikal MJ. "Determination of end point of primary drying in freeze-drying process control." ''AAPS PharmSciTech'' 11(1):73–84 (2010).</ref>
100	<ref name="chang2009">Chang LL, Pikal MJ. "Mechanisms of protein stabilization in the solid state." ''Journal of Pharmaceutical Sciences'' 98(9):2886–2908 (2009).</ref>	113	<ref name="chang2009">Chang LL, Pikal MJ. "Mechanisms of protein stabilization in the solid state." ''Journal of Pharmaceutical Sciences'' 98(9):2886–2908 (2009).</ref>
101	<ref name="murphy2005">Murphy DM, Koop T. "Review of the vapour pressures of ice and supercooled water for atmospheric applications." ''Quarterly Journal of the Royal Meteorological Society'' 131(608):1539–1565 (2005).</ref>	114	<ref name="murphy2005">Murphy DM, Koop T. "Review of the vapour pressures of ice and supercooled water for atmospheric applications." ''Quarterly Journal of the Royal Meteorological Society'' 131(608):1539–1565 (2005).</ref>