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Modern Lyo Cycle Optimization“Hot” and “Cold” Spot Determination by Wireless Real-Time Temperature Measurementas Process Analytical Technology (PAT) Tool

Dr. Andrea Weiland-Waibel . Explicat Pharma GmbH, Hohenbrunn

Korrespondenz: Dr. Andrea Weiland-Waibel, Explicat Pharma GmbH, Georg-Knorr-Str. 4, 85662 Hohenbrunn;e-mail: [email protected]

AbstractTraditional lyo cycle development leads to a predetermined program that usually issubject of process validation. As a consequence this cycle needs to be applied for thefabrication of the product under all circumstances. If for any reasons e. g. only a part ofa total batch size can be manufactured, no adaptations are possible, i. e. the shorteningof the cycle is not allowed due to regulatory compliance.This article demonstrates a new conceptual design to the development and modern vali-dation of lyo cycles applying process control by determination of Product Temperature(TP) in critical positions (“hot” and “cold” spots) which allows for adaptation of the lyocycle. Furthermore usage of these positions in development scales during scale-up androutine production is shown.

1. Introduction

Modern development following ICHQ8, Q9 and Q10 in the context offreeze drying is based on the objec-tive to design a lyophilization cycleapplying a systematic and scientificapproach instead of trial and error.

As described by Dr. Henning Gies-eler [1] the coupling link betweenformulation and process is the phys-icochemical behaviour of the formu-lation resulting in a maximum allow-able Product Temperature TP duringdrying.

Product Temperature TP is of ut-most importance in Freeze Drying as. TP is a critical product parameterwhich determines importantproduct quality attributes such asphysical appearance, residualmoisture, storage stability, recon-stitution time, etc.

. TP cannot be controlled directly,but is influenced by shelf temper-ature, chamber pressure, productresistance and various other fac-tors such as super cooling, envi-ronment, etc.

. TP must not exceed the criticalformulation collapse temperature

TC or eutectic temperature TE dur-ing primary drying to avoid col-lapse and meltback.

In this article the basis for a newapproach to the development ofmodern lyo cycles is shown. ProductTemperature determination by ther-mocouples and by wireless temper-ature measurement in the critical po-sitions (“hot” and “cold” spots) of thefreeze dryer is applied. TP as deter-mined by process analytical technol-ogy devices may be used as a processcontrol (feedback system) to run thelyo cycle which ultimately allows forflexibility in the adaptation of lyocycles that are within the regulatoryspace.

2. PerformanceQualification as Basis andFirst Step in the Design ofModern Lyo Cycles

2.1 Dynamic PerformanceQualification (PQ)Performance Qualification (PQ) playsan important role in modern ap-proaches towards process validationfrom as early as lab scale devel-

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TechnoPharm 5, Nr. 3, 130–137 (2015)© ECV . Editio Cantor Verlag, Aulendorf (Germany) 1Weiland-Waibel . Lyo Cycle Optimization

Autor

Dr. Andrea Weiland-Waibel

Dr. Andrea Weiland-Waibel is Managing Director,QP and founder of Explicat® Pharma GmbH andexpert in CMC project management. She is a fre-quent lecturer and holds several patents in phar-maceutical development, GMP-related subjectsand lyo formulation and previously was Head ofPharmaceutical Technology at Pfizer.Explicat Pharma has been assigned several projectsin relation to lyo products applying the modernprocess validation approach, including lyo cycleRobustness Testings.

Key Words. Lyo cycle. Critical positions. Process control. Product temperature. Critical product parameter

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opment up to routine manufacture,particularly in aseptic lyophilizationtechnology. PAT (Process AnalyticalTechnology) tools are crucial in mon-itoring, optimizing and validatingsuch freeze drying processes espe-cially if the same tool can be usedat all scales.

The present case study of a per-formance qualification shows relevanttemperature differences between sin-gle lyo vial position (centre vs. edge)and across different shelves (depend-ing on distance to condenser) –withina commercial scale lyophilizer. Astandard lyo cycle had been instru-mented with a real-time PAT tool:Wireless Temperature Remote Inter-rogation System (TEMPRIS®). Thedefinition of “hot” and “cold” spots

(HCS) [2,3] during Performance Qual-ification employing a “single-vialmethod” proved to be practical andreliable during routine use, particu-larly for freezing step optimizationand primary drying end-point deter-mination as demonstrated duringscale up and transfer.

2.2 Materials & MethodsExperiments were conducted at apharmaceutical manufacturer´s siteon a production scale freeze dryer(8,78 m2, 9+1 shelves) running a text-book lyo cycle, fully loaded with 2Rvials, each filled with 1 ml WFI(Water For Injection). Analytics wereconducted using 16 TEMPRIS size Ssensors (Fig. 1), one InterrogationUnit (Fig. 2) and TEMPRIS Data

Server (software). Sensors wereplaced in the middle of vial and vialsat varying centre or edge positionson shelves Nos. 2, 4, 5 and 6 top tobottom (Fig. 3).

2.3 ResultsProduct temperature curves at thebottom of vials (TPb) from the 16 sen-sor positions were plotted and com-pared (Fig. 4). The overall critical“cold” spot is positioned at the bot-tom of the freeze dryer with a mini-mum distance to the condenser. Theoverall critical “hot” spot is located atthe edge on the top shelf of the freezedryer with a maximum distance tothe condenser. Temperature differ-ences ranged from 3 °C to 4 °C (freezi-ing/annealing, Fig. 5) and 3 °C to 8 °C


TechnoPharm 5, Nr. 3, 130–137 (2015)© ECV . Editio Cantor Verlag, Aulendorf (Germany)2 Weiland-Waibel . Lyo Cycle Optimization

Fig. 1: Vial with wireless temperature sensor(Source of all figures and tables: iQ-mobilsolutions GmbH).

Fig. 2: Interrogation Unit (IRU-2). Fig. 3: Sensor positions.

Fig. 4: 16-sensor overlay plot representing temperature measurements from total instrumentation.

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(primary drying, Fig. 6) betweenoverall “hot” spot at maximum dis-tance to condenser and overall “cold”spot.

2.4 DiscussionAs could be shown by the presenteddata (Fig. 7) of a performance quali-fication study the differences in heat

transfer in edge and central positionsare significant as Product Tempera-ture at the bottom TPb varies signifi-cantly between the positions. To lo-cate the extreme positions in a givenfreeze dryer is the first step to applythe TP determination in these posi-tions to optimize the lyo cycle anduse TP for scale up and transfer.

3. TP Determination forLyo Cycle Development inLab Scale

3.1 Process Robustness TestingBased on a formulation developedprocess robustness was assessed.Process Robustness is defined as “abil-ity of a process to tolerate variability


Fig. 6: Overlay of overall “hot” spot (shelf x, position y) and overall “cold” spot (shelf z, position z) during drying.

Fig. 5: Overlay of overall “hot” spot (shelf x, position y) and overall “cold” spot (shelf z, position z) during freezing/annealing.



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of materials and changes to the proc-ess and equipment without negativeimpact on quality”[1]. The lyo cycleRobustness Testings were performedaddressing critical process parame-ters (CPsP) such as Pressure (P), watervapour concentration (c) and gas flowvelocity (u) which yield in criticalproduct parameters (CPtP) such asTP (Product Temperature), ProductResistance (Rp, area normalized prod-uct resistance), Residual Moisture(RM, %). As acceptance criteria forthe testings as critical quality attribute(cQA) the physical appearance was ap-plied as assessed by 100 % visual in-spection. The lyo product must havecorrect cake volume and appearance(Fig. 10). Not acceptable cakes are

“meltback” (Fig. 8), “collapse” or“shrinkage” (Fig. 9).

Robustness Testings carried out tofind out the critical process parame-ters (CPtP) and relating TP in thelaboratory were done in relation tothe following predefined conditions:Vials chosen for commercial scale,need to apply trays for loading andunloading of the production freezedryer and to allow for an estimatedprediction of lyo cycle time (i. e. notmore than 70h lyo cycle for commer-cial viability).

3.2 Materials & Methods ofProcess Robustness TestingsLyostar II SP Scientific – 0.43 m2 shelfarea; 3 shelves, condenser tempera-ture (-85 °C); equipped with MTM(Manometric Temperature Measure-ment) for pressure rise measure-ments and SMART software;

Thermocouples: calibrated T-TypeCopper / Constantan from Omega(Fig. 11);

TEMPRIS wireless temperaturesystem;

Vials: 26.5 mm diameter, clear &amber glass ex Schott, hydrolyticclass I;

Stoppers: 20 mm bromobutylstoppers, igloo.

An optimized cycle based on pre-vious experience during develop-ment phase was used as basis forcycle variations. A total of 11 robust-ness runs (Table 1) were done withdifferent shelf temperatures.

3.3 Results of Lyo RobustnessTestingsThe crystalline matrix of the formu-lation (see Fig. 13) allows drying atTpb >Tg’ (glass transition – temper-ature of the maximally freeze-con-centrated solute of a glass which stillcontains a specific fraction of unfro-zen water) [1] of the formulation.Within the Robustness Testings thevariation of the shelf temperature Tswas tested. The annealing step needsto be sufficiently long to obtain a uni-form crystalline matrix. Usage oftrays for loading has a significant im-pact – the annealing time needs to beincreased (Fig. 12).

The testings led to a final opti-mized lyo cycle in the lab as basisfor the transfer into production scaleand was discussed with the expertsof production site.



Fig. 7: Overlay of overall “hot” and overall “cold” spot across the entire run.

Fig. 8: Not acceptable meltback cake. Fig. 9: Collapse/shrinkage cake. Fig. 10: Acceptable elegant cake.



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3.4 Use of TEMPRIS forScale up/ProductionTo support the transfer TEMPRISwas applied. In opposition to ther-mocouples this is a wireless batteryfree real time temperature measure-ment system. Its sensors can be steri-lized and they can be placed andpositioned aseptically within ALUSand Isolators in the critical positionsof the freeze dryers.

For the transfer, the final runs of lyocycle development were performedwith this software to allow for a directcomparison of the runs in the lab withthe production (Fig. 14).

4. Process QualificationRun in Production Scale

4.1 Scale-up descriptionA direct upscale from approximately430 vials (Lyostar II, 3 shelves, seeFig. 14) to approximately 45000 vialson 18 shelves, 30 m2 was performed(Fig. 15).

The cycle used in production wasagreed mutually with the contract ma-nufacturing organization specialists.

4.2 Materials & MethodsCommercial manufacturing site 18shelves freeze dryer with 30 m2;

TEMPRIS system: equipped with16 sensors. Installation see Fig. 15and Fig. 16.

Fig. 12: Consequences of alu tray use in relation to the annealing step.

Fig. 11: Typical loading pattern (clear glassvials instrumented with thermocouples).

Table 1

Lyo Cycle Robustness Testing – Example of Cycles



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Same formulation and vials as inlyo cycle development.

4.3 Results16 sensors showing the TP variability:Sensors were located at different po-sitions (“hot” and “cold” spots – asobtained by previous performancequalification) shelves 1, 3, 5, 6, 9, 12,15, 18, centre and front door (edge)positions.

As can be seen in figure (Fig. 17)the approximate maximum differ-ence in the freezing step is around5 °C and in primary drying slightlymore than 20 °C.

4.4 DiscussionTEMPRIS feeding back the TP valueof the critical positions into thescada system (supervisory controland data acquisition) controls theprocess by indicating the end of therespective process step. By this theTP over time as a critical productparameter in the critical positionsis the leading parameter of the cycle.

To fulfil regulatory acceptance thesoftware has to be already appliedduring the development and processqualification of a lyo cycle. By the lyocycle robustness studies and processqualification in production scale aprocess design space can be justifiedand presented in the relevant regula-tory section 3.2.P.3 manufacture(quality section of the common tech-nical document).

On the basis of an accepted proc-ess space this process space may beused for adaptations in routine man-ufacturing, e. g. in case of a partialload to speed up the freeze dryingperiod. As a TP over time regardingcritical temperatures is kept con-stant the product quality is not af-fected.

5. Conclusion

The new approach is that the lyocycle is process controlled by run-ning the lyo cycle through TP in crit-ical positions. This means the initialfreezing step being finished when thevials positioned at the critical “hot”

spot positions are reaching the ac-ceptance TP for the freezing stepand the primary drying is at its end

by complete sublimation of the icealso of the vials positioned at thecritical “cold” spot positions by



Fig. 15: TEMPRIS installation from outsidethrough an unused flange.

Fig. 16: TEMPRIS antenna installation in thefreeze dryer.

Fig. 14: Final optimized lab cycle run with TEMPRIS – Lyo Cycle Robustness Run # 11.

Fig. 13: XRPD (Xray Powder Diffraction) Analysis. The correct crystalline matrix and no sig-nificant difference of the positions is seen.


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reaching the acceptance TP allows fora real time process controlled cycleadaptable among all scales.

TP as the critical product parame-ter that is directly linked to productquality attributes should be usedover the lyo cycle as an inline feed-back process control in modern lyocycle design. TP acceptance criteriafor the freezing step, primary andsecondary drying defined for the ex-

treme positions can be controlledand by this the product quality canbe predicted and kept across allscales of lyophilization. This articleshowed the first step to this context,which is to determine the extremepositions in a given freeze dryer asa dynamic performance qualificationstudy. As a second step the usewithin scale-up and modern processvalidation was demonstrated.

References[1] Gieseler, H. in Encyclopedia of Pharma-

ceutical Science and Technology, FourthEdition, Quality by design (QBD) in FreezeDrying (2013)

[2] Rambhatla S, Tchessalov S, and Pikal MJ.Heat and mass transfer scale-up issuesduring freeze-drying, III: Control andcharacterization of dryer differences viaoperational qualification tests. AAPSPharm Sci Tech. 2006; 7(2): E1-E10.

[3] Hibler S, Wagner C, and Gieseler H. Vialfreeze-drying, Part 1: New insights intoheat transfer characteristics of tubing andmolded vials. J Pharm Sci 2011; 101(3):1189-1201.


Fig. 17: Cycle from Fig. 14 adapted for production scale (Process Qualification Run).

Redaktion: Chefredakteur: Claudius Arndt, Redakteur: Jens Renke. Verlag: ECV · Editio Cantor Verlag für Medizin und Naturwissenschaften GmbH, Baendelstockweg 20,88326 Aulendorf (Germany). Tel.: +49 (0)8191-9857812, Fax: +49 (0)8191-9857819. e-mail: [email protected]. http://www.ecv.de.Herstellung: Reemers Publishing Services GmbH / Holzmann Druck GmbH & Co. KG. Alle Rechte vorbehalten.


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Redaktion: Chefredakteur: Claudius Arndt, Redakteur: Jens Renke. Verlag: ECV · Editio Cantor Verlag für Medizin und Naturwissenschaften GmbH, Baendelstockweg 20,88326 Aulendorf (Germany). Tel.: +49 (0)8191-9857812, Fax: +49 (0)8191-9857819. e-mail: [email protected]. http://www.ecv.de.Herstellung: Reemers Publishing Services GmbH / Holzmann Druck GmbH & Co. KG. Alle Rechte vorbehalten.

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Modern Lyo Cycle Optimization - Explicatexplicat.biz/docs/modern-lyo-cycle-optimization.pdf · mined by process analytical technol-ogy devices may be used as a process control (feedback