Dicoias CryoSurge Smart Annealing (DCSA)Annealing guided by the product’s own CryoSurge, before the deep freeze

01The rule

02The sequence

With the example figures Bogdan Dicoias gave for it:

1. 01Product cools to −18 °C.−18 °C
2. 02CryoSurge detected at −18 °C.T_CS = −18 °C
3. 03The natural exotherm raises the product to −12 °C.T_CP = −12 °C
4. 04Product cools again to −18 °C.−18 °C
5. 05DCSA initiates controlled reheating towards the recorded natural peak, −12 °C.−12 °C
6. 06The prescribed annealing hold.hold
7. 07Cooling to the selected final ULT target, for example −40 °C.−40 °C

03Several holders, one decision

The Lyochrysalis carries its load in several holders, each with its own probe. The annealing target is common and the reversal is personal: T_ANNEAL is the lowest credible recorded peak among the holders — never a plain average, so no holder is warmed above its own natural peak — and each holder reverses at its own recorded onset. When only two holders show an identifiable CryoSurge, DCSA uses those two and keeps monitoring and protecting the third. A missing spike is never taken as proof of crystallisation or of failure: a holder without a credible event is protected, never certified.

04How DCSA differs from conventional annealing

See the three routes side by side, with their thermal travel, on the home page.

05Constraints

Heat without overshoot. The controlled warming is delivered in pulses while the heat-transfer fluid keeps circulating, so it cannot overshoot through the delayed response of the fluid. In S3Pulse’s recorded run the circulation pump is commanded on, and read back on at its relay, through the whole warming, the hold and the final freeze while the heater pulses.

06What DCSA does to the ice

DCSA restructures the ice at the moment the formulation has just crystallised, and with it the cake morphology and the drying that follows. Annealing is known to work through two processes with different kinetics, Ostwald ripening of the ice and the relaxation of the glassy freeze-concentrate (Kharatyan et al. 2022, PMID 35745749); the moment of nucleation already changes the ice, because containers that nucleate first ripen longer (Patel et al. 2009, PMID 19937284); and in one antibody formulation controlled nucleation shortened primary drying more than annealing at the same temperature did (Wang et al. 2022, PMID 35613684).

References

1. Searles JA, Carpenter JF, Randolph TW. Annealing to optimize the primary drying rate, reduce freezing-induced drying rate heterogeneity, and determine T(g)' in pharmaceutical lyophilization. J Pharm Sci 2001;90(7):872-87. PMID 11458336
2. Kharatyan T, Gopireddy SR, Ogawa T, Kodama T, Nishimoto N, Osada S, Scherließ R, Urbanetz NA. Quantitative Analysis of Glassy State Relaxation and Ostwald Ripening during Annealing Using Freeze-Drying Microscopy. Pharmaceutics 2022;14(6):1176. PMID 35745749
3. Patel SM, Bhugra C, Pikal MJ. Reduced pressure ice fog technique for controlled ice nucleation during freeze-drying. AAPS PharmSciTech 2009;10(4):1406-11. PMID 19937284
4. Wang J, Searles JA, Torres E, Tchessalov SA, Young AL. Impact of Annealing and Controlled Ice Nucleation on Properties of A Lyophilized 50 mg/ml MAB Formulation. J Pharm Sci 2022;111(9):2639-2644. PMID 35613684
5. Chouvenc P, Vessot S, Andrieu J. Experimental study of the impact of annealing on ice structure and mass transfer parameters during freeze-drying of a pharmaceutical formulation. PDA J Pharm Sci Technol 2006;60(2):95-103. PMID 16696192