In this final part of the article on section 8 we will look at Sterilization processes.
The selection of a sterilization process should be based on scientific principles and validated to demonstrate repeatability and reliability. There are various sterilization processes that can be used. The method of choice is moist heat. Each cycle should have a unique reference and any failed or deviating sterilization process should be investigated.
For heat sterilization monitoring, temperature probes should be controlled within a defined temperature range. Sterilizers need to be able to detect non-conforming parameters and abort or fail the cycle. For parametric released products, a robust sterility assurance system should be applied to product lifecycle validation and during routine monitoring and be periodically reviewed (see Annex 17).
For moist heat processes, Annex 1 now adds superheated water systems for fluids load cycles. Just like steam, the heated water should consistently reach all required contact points and validation should demonstrate this. The water nozzles need to be regularly checked for blockages. Steam in place (SIP) systems for fixed pipework like vessels, lyophilizers and similar equipment also need validating to show effective steam contact. Monitoring should include the condensate drain temperature as the excessive condensate produced during sterilization can suppress temperatures. Porous load autoclave and lyophilizers have air removal stages prior to and during sterilization. Autoclaves should include a daily air removal test and or a cycle air detector system as this can impact product sterilization. Loads should be designed to support effective air removal and be free draining to prevent the build-up of condensate. On completion of moist heat cycles there should be post sterilization checks for damage, packaging material integrity and moisture. Non-compliant items should be segregated and investigated. Terminally sterilization cycles should also be designed to prevent distortion and damage of non-rigid containers which could otherwise lead to pack integrity breakdown.
Dry heat processes are important in the thermal removal of endotoxin/pyrogen and preparation of components for aseptic filling. Routine sterilizing conditions should give reproducible level of lethality and endotoxin removal etc. Air pressure differentials should be assessed for tunnels as it is important to prevent ingress to the grade A/B areas. Any airflow changes should be assessed to ensure the heating profile is maintained. HEPA filter integrity should be tested and certified at least biannually. Critical process parameters, for example, belt speed or dwell time within the sterilizing zone, minimum and maximum temperature and heat penetration of the material need to be validated.
About the author
Andy Martin
Andy started working in the Pharmaceutical industry in 1985 as a lab technician for Smith & Nephew. Following this, he had a number of roles culminating when he took over as QA Microbiology Manager. In 2003 he moved into Pharmaceutical Training and then in 2007 he moved back into Microbiology when he took up the position of Microbiology Manager for Catalent Pharma Solutions. Since 2012 he has operated as a consultant specialising in Microbiology and Quality Systems.
Training courses on Annex 1
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The significant changes for sterilization by radiation has been to remove much of the content from annex one as it was duplicating Annex 12.
Sterilization with ethylene oxide has seen some additions including the quality of steam used to condition load, conditioning time should be balanced against minimizing the time before sterilization, BIs needing to be placed at defined validated worst-case locations and the need for post sterilization load should be aerated to removal of residual gas and reaction products.
The final process, and that which created the most contention is sterile filtration used for sterilizing filterable fluids. The components of a filtration system should be carefully selected considering the need to control fibres, particles, adsorption of product components and extractables and leachables.
Design guidance is also provided, for example system design should allow operation within validated process parameters, minimize the number of aseptic connections, and permit in-place integrity testing. The reason for the greatest contention was the inclusion of the pre-use post sterilization integrity test or PUPSIT to to check for damage and loss of integrity caused by the filter preparation prior to use. PUPSIT may not always be possible for example for very small volumes of product so a risk assessed alternative approach can be implemented along with appropriate controls. Such controls include for example, an in-depth knowledge of the filter sterilisation process including the product type, particle burden and any risk that product may alter integrity testing values which could prevent the detection of a non-integral filter. Other knowledge and controls include the supply chain including contract sterilisation facilities, and defined transport mechanisms including packaging of the sterilised filter.
After use, an integrity test is needed before removing the element from a housing. Integrity of the filter should correlate to the microbial retention capability of the filter established during validation. Water intrusion test now added to list range of tests.
Multi-filter systems can be designed as single sterilizing units or to include redundancy. In the former, all filters need to pass integrity testing after use. For Redundant and where validation has shown only one filter is required, Integrity testing is only required on the primary filter unless it fails. In case of a failure a redundant filter can be tested, and an investigation completed. An aseptic bioburden sample immediately prior to the final sterile filtration or first filter in redundant systems should be taken. In campaign manufacture the filtration process should for example be risk assessed and documented for duration of use, be validated to show duration of use doesn’t compromise filter or filtrate quality and to determine maximum duration of use.
Finally, critical sterile gas and air vent filters should be tested prior to disassembly. Noncritical gas and air filters should be tested at installation and when replaced (long term use).
In the next article, we will move onto section 9.
About the author
Andy Martin
Andy started working in the Pharmaceutical industry in 1985 as a lab technician for Smith & Nephew. Following this he had a number of roles culminating when he took over as QA Microbiology Manager. In 2003 he moved into Pharmaceutical Training and then in 2007 he moved back into Microbiology when he took up the position of Microbiology Manager for Catalent Pharma Solutions. Since 2012 he has operated as a consultant specialising in Microbiology and Quality Systems.
Training courses on Annex 1
There are a number of half-day workshops organised to take you through the changes in more detail and to look at how they relate to your organisation.
