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Steam Sterilisation of BFS containersin AutoclavesPeter ÅkermanSenior AdviserAstraZeneca, Sweden OperationsBFS IOA Training Seminar – Kunming - March 2018

Content Regulatory requirements Considerations for Choice of Process Cycle Design Practical case studyBFS IOA Training Seminar – Kunming - March 2018

IntroductionAseptic fill vs. Terminal Sterilisation ? FDA – Guideline for ’Aseptic Processing’ (2004)” sterile drugs should be manufactured by asepticprocessing only when terminal sterilization is not feasible.However, some final packaging may afford some uniqueand substantial advantages that would not be possibleif terminal sterilization were employed.”BFS IOA Training Seminar – Kunming - March 2018

IntroductionAseptic fill vs. Terminal Sterilisation ? European Pharmacopoeia”Wherever possible a process in which the productis sterilised in its final container (terminal sterilisation) ischosen.”“It is recommended that the choice of the container is suchas to allow the optimum sterilisation to be applied.”BFS IOA Training Seminar – Kunming - March 2018

IntroductionAseptic fill vs. Terminal Sterilisation ? EMEA Guideline (April 2000)Decision Trees for the Selection ofSterilisation Methods (CPMP/QWP/054/98)”The use of an inappropriate heat-labile packagingmaterial cannot in itself be the sole reason for adoption ofaseptic processing.”BFS IOA Training Seminar – Kunming - March 2018

IntroductionAseptic fill vs. Terminal Sterilisation of BFS ? Aseptic fill most flexible for choice of container /material no investment in autoclave needed- filling in grade A zone with min. grade C* background- extensive environmental monitoring- media fills twice a year- restrictions in fill time, interventions etc.* using grade B clothingBFS IOA Training Seminar – Kunming - March 2018

IntroductionAseptic fill vs. Terminal Sterilisation ? Terminal sterilisation filling in grade C or even grade D less environmental monitoring no media fills longer fill time- investment in autoclave needed- more careful selection of suitable polymer materialsBFS IOA Training Seminar – Kunming - March 2018

IntroductionAseptic fill vs. Terminal Sterilisation ? It is well recognized that Blow-Fill-Seal is an excellent techniquefor aseptic processing . .but due to it’s superior flexibility in container design and lowrisk for particulate contamination, it is alsoa most suitable technique for filling containers that shouldundergo terminal sterilisationBFS IOA Training Seminar – Kunming - March 2018

IntroductionAseptic fill vs. Terminal Sterilisation ?APIHeat erilisation(Aseptic fill)Terminalsterilisationor Aseptic fillAPIHeat sensitiveAseptic fillAseptic fillBFS IOA Training Seminar – Kunming - March 2018

Regulatory Demands If a terminal sterilisation process have been choosen;- what should be included in the regulatorysubmission for a new product ?BFS IOA Training Seminar – Kunming - March 2018

Regulatory requirements forMoist Heat SterilisationFDA – Guidance for Industry; Submission Documentation forSterilization Process Validation in Applications for Humanand Veterinary Drug Products (1994). Description of the Process and Product Thermal Qualification of the cycle Microbiological Efficacy of the Cycle Container Closure and Packaging Integrity Bacterial Endotoxins Test and Method Sterility Testing Methods and Release CriteriaBFS IOA Training Seminar – Kunming - March 2018

Regulatory requirements forMoist Heat SterilisationEU GMP (Eudralex)– Annex 1 (2008) ”All sterilisation processes should be validated” ” .its efficacy in achieving the desired sterilising conditionsin all parts of each load to be processed should bedemonstrated by physical measurements and by biologicalindicators where appropriate.” ” the whole of the material must be subjected to therequired treatment and the process should be designed toensure that this is achieved” ”Validated loading patterns should be established for allsterilisation processes”BFS IOA Training Seminar – Kunming - March 2018

Regulatory requirements forMoist Heat SterilisationUSP/NF Minimum demand 10-6 probability for microbial survivors ”Overkill” approach – typical reduction to 10-12 orF0 12, (normally 121.1ºC for 12 min)Ph Eur Minimum 121.1ºC for 15 min- ”Other combinations of time and temperaturemay be used .”BFS IOA Training Seminar – Kunming - March 2018

Design Considerations How to design your moist heat process and chooseappropriate equipment ?BFS IOA Training Seminar – Kunming - March 2018

Design considerations Can Overkill approach be applied ? Limitations in temperature (API container) ? Choice of material for container Standard PE grades normally not suitable Heat resistant PE grades exists Most PP grades can allow 121 ºC Example - F0 15 can be achieved by 121 ºC for 15 min or 112 ºC for 122 min or 108 ºC for 5 hBFS IOA Training Seminar – Kunming - March 2018

Choice of AutoclaveProblem: When heating up a flexible container, the internal pressurewill try to expand the volume of container (i.e. risk fordeformation !) Pint PH2O Pair PH2O saturated steam pressure Pair pressure increase due to the ’Ideal-gas’ law In a traditional vacuum autoclave Pcmb PH2O!BFS IOA Training Seminar – Kunming - March 2018

Choice of AutoclaveSolution: Air / Steam mixture autoclave(Counter pressure autoclave) Can apply a counter pressure to balance the internalpressure in the container This has to be relative to the actual temperature Homogeneity and heat transfer is achieved by fanscreating high turbulence in the chamberBFS IOA Training Seminar – Kunming - March 2018

Choice of AutoclaveAdvantages of Air/Steam autoclaves; Counter pressure gradually increased when temperatureincreases A constant pressure applied during Sterilisation phase Gradually decreasing pressure during cool-down, which alsoallows efficient drying Air / Steam autoclaves can be utilised also forother type of sterilisation processes where a dry product isrequired after processingBFS IOA Training Seminar – Kunming - March 2018

Case study How to design and validate a autoclave process for a blisterpacked BFS ampoule ?BFS IOA Training Seminar – Kunming - March 2018

Case StudyBackground – Product to be sterilised BFS ampoule in PP (Polypropylene) Two sizes – 10 and 20 mL Absolutely no deformation allowed Packed in a Blister pack and that must guaranteealso a sterile outside of the ampoule Should be completely dry after processing Minimum sterilisation target F0 15BFS IOA Training Seminar – Kunming - March 2018

Case StudyBackground – Autoclave and load considerations Counter Pressure Autoclave Three fans in the ceiling dual heat exchangers Process controlled by reference sensors Individual control of each section of the chamber Load pattern designed to allow free space between each layer ofproduct Ampoules autoclaved in upright position to facilitate drainage ofcondensed steam Minimum load ½ pallet, maximum 3 palletsBFS IOA Training Seminar – Kunming - March 2018

Development of ProcessAs a base a standard process-programme from the supplierwas used Heating with dry air to a temperature below 100º C Final heating to sterilisation temperature 121º C by combinedsteam and air mixture Sterilisation at constant conditions at 121º C until F0 targetreached Drying phase in combination with a slow cooling down Final cooling phase to below 40º CBFS IOA Training Seminar – Kunming - March 2018

Development of ProcessFirst step is further development and fine-tuning of Processparameters to achieve a perfect process Establish design for the reference sensors Establish ramp-up speed for temperature and pressure Establish temperature for exchange of phase Establish counter-pressure at exposure phase Establish conditions for drying phase Establish ramp-down speed for temperature and pressure Fan speed in different phasesBFS IOA Training Seminar – Kunming - March 2018

Development of Process In total more than 20 test runs were needed The development work is extremely important to gainknowledge of how the combination of the autoclave and theactual product interacts together This information is mandatory to lay down the processprogramme to be used for the validation It is also valuable to have this understanding if some deviationswill occur in the futureBFS IOA Training Seminar – Kunming - March 2018

ValidationConsists of 5 important steps; Installation Qualification Operational Qualification Thermo mapping study Performance Qualification Process Validation BatchesBFS IOA Training Seminar – Kunming - March 2018

Operational QualificationSome examples of critical tests Empty chamber temperature distribution Fan speed and rotation Media consumption Cooling capacity Calibration of sensors Verification of process control programmesBFS IOA Training Seminar – Kunming - March 2018

Thermo mapping studiesTo get full understanding of temperature variations in the load Identify potential cold spots Identify potential hot spots (where applicable) Study different load patterns- this is especially important for air/steam processes Utilise maximum number of sensorsBFS IOA Training Seminar – Kunming - March 2018

Thermo mapping studiesIn the actual case; Two Kaye Validator equipments were used- each one offered 36 sensors Five possible load patterns were evaluated(½, 1, 1½, 2 and 3 full pallets) Both ampoule sizes tested individually Biological indicators were also applied in the loadBFS IOA Training Seminar – Kunming - March 2018

Thermo mapping studiesThe results from Thermo mapping showed that; No significant cold or hot spots were detected 20 mL ampoules required longer process time 1½ pallet was the most critical load pattern No deformation of the ampoules occurred No risk for leakage after processing It was found to be some very small amountsof condensate on the inside of a few blister packsafter end of processBFS IOA Training Seminar – Kunming - March 2018

Thermo mapping studiesThe results from Thermo mapping where then used toestablish the conditions for PQ tests The recommendation for number of sensors were 36 formaximum load, and 12 for minimum load For each thermo sensor also two Biological and oneChemical indicator should be used (”Sensor Package”) Process parameters confirmed and criteria for evaluation ofeach process established Number of qualification runs to include in PQBFS IOA Training Seminar – Kunming - March 2018

Load PatternsAlternative load patternevaluatedBFS IOA Training Seminar – Kunming - March 2018

Example of ”Sensor package”Chemical indicatorInocculated surfaceTemp. sensor in solutionBiological indicatorBFS IOA Training Seminar – Kunming - March 2018

Process QualificationAim to verify the reproducibility for the Process For 20 mL ampoules – 3 runs for each of the three loadpatterns (minimum, middle and maximum) For 10 mL ampoules only 3 runs of maximum load (samereference sensor to be used) in total 12 runsBFS IOA Training Seminar – Kunming - March 2018

Results of the Process QualificationAll runs fulfilled the acceptance criteria except for one runwhere F0 15 was not achieved in one position !Since no explanation could be found, this was seen as normalvariation in the process, and therefore it was decided toincrease the control limit for F0 to 20 for coming routineproductionA final version of the SOP for the autoclave process were issuedBFS IOA Training Seminar – Kunming - March 2018

Process Validation Batches Normal commercial production batches Since the products are considered to be similar this meant 3batches of each 10 and 20 mL The batches were of course run by ordinary well trainedproduction personnel according to BPR and the final versionof the SOP After approval of these batches the final Validation Reportwas issues and approvedBFS IOA Training Seminar – Kunming - March 2018

Critical parameters to evaluate Time to reach phase transition 1 (air to air/steam phase) Time to reach phase transition 2 (into exposure phase) Total heat up time Time in exposure phase Pressure ramp during different phases Drying and Cooling performanceBFS IOA Training Seminar – Kunming - March 2018

Some Final Words A concept paper to establish a harmonised guideline for the selectionof sterilisation processes, were presented by EMA in 2014 ”Guideline on the sterilisation of the medical product, activesubstance, excipient and primary container” A draft for public consultation was sent out in april 2016(EMA/CHMP/CVMP/QWP/BWP/850374/2015) the intention is to further clarify recommendations for Sterilisation ofmedical products When (if) approved, this document should replace the ”Decision tree”from 1998, (CPMP/QWP/155/98)BFS IOA Training Seminar – Kunming - March 2018

Thanks for your attention !Any questions or comments ?BFS IOA Training Seminar – Kunming - March 2018

Two Kaye Validator equipments were used - each one offered 36 sensors Five possible load patterns were evaluated (½, 1, 1½, 2 and 3 full pallets) Both ampoule sizes tested individually Biological indicators were also