usp and its impact on microbiology

PowerPoint Presentation

USP and its impact on Microbiology

Dr. Tim SandlePharmaceutical Microbiology: http://www.pharmamicroresources.com

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IntroductionEM guidanceBackground to USP Main changes and debatesMethod limitationsIncident ratesFrequencies of monitoringLocations of monitoringOther changesRegulatory issuesRapid methodsPharmaceutical Microbiology: http://www.pharmamicroresources.com

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Sources of EM GuidanceEU GMP - last EM revision 2009; new annex 1 2016?FDA aseptic filling guide (2004)PDA Technical Report (2014, 3rd revision)ISO 14698 (1998). Future update?USP (2011, published 2012)Pharmig Current Review (2010)PHSS Biocontamination control guide 2015Pharmaceutical Microbiology: http://www.pharmamicroresources.com

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Sources of EM GuidanceISO 14698Under long-term reviewPossible development to a viable cleanroom classification standard (like ISO 14644)No other standard is likely to be reviewed in the short-termPharmaceutical Microbiology: http://www.pharmamicroresources.com

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ISO 14644ISO 14644 Parts 1 and 2 revised in December 2015A standard for cleanroom classification.Some detail about on-going monitoring.Does not cover viable monitoring at all.Changes:New look-up tablesIncrease in counter locationsChanges to sampling volumesEach individual location must pass.More risk based.Pharmaceutical Microbiology: http://www.pharmamicroresources.com

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USP (2012)USP Revision began in 2005Objectives of USP committee:Focus the chapter on environmental monitoring only, removing information relating to aseptic process validation.Focus the document exclusively on the monitoring of aseptic environments.Reconsider the alert and action level (limit) concept.Effective 1st May 2012, 35th edition of the USP

Pharmaceutical Microbiology: http://www.pharmamicroresources.com

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Main changes

Former title:

Microbial Control and Monitoring EnvironmentsUsed for the Manufacture of Healthcare Products

Revised title:

Microbiological control and monitoring of aseptic processing environmentsPharmaceutical Microbiology: http://www.pharmamicroresources.com

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Main changesScope:Pharmaceutical sterile productsBulk sterile drug substancesSterile intermediatesExcipientsEnvironmentsConventional clearoom with UDAFBlow-fill-sealRABSIsolatorPharmaceutical Microbiology: http://www.pharmamicroresources.com

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Main changesThe emphasis on the word aseptic in the introduction implies that the chapter is not applicable to all sterile products.This means that terminally sterilised products are outside the scope of the chapter.Pharmaceutical Microbiology: http://www.pharmamicroresources.com

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Main changesBy aseptic a low level of contamination is acknowledged:

an expectation of zero contamination at all locations during every aseptic processing operation is technically not possible and thus is unrealisticPharmaceutical Microbiology: http://www.pharmamicroresources.com

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Main changesUSP notation system dropped: M3.5 etc. And old FDA 209E classes e.g. Class 100, Class 10,000)Replaced by ISO 14644 classes in the operational stateDifference with EU GMP:Class 5=EU GMP Grade AClass 7=EU GMP Grade BClass 8=EU GMP Grade CPharmaceutical Microbiology: http://www.pharmamicroresources.com

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Main ChangesRelative risks

Picture showing on how process separation and product protection interact (adopted from Bioquell U.K Ltd).


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Main changesThe design and construction of clean rooms and controlled environments are covered in ISO 14644.ISO 14644 stipulates the total particulate counts required for a clean environment to meet the defined air quality classifications. USP accepts this standard verbatim.Pharmaceutical Microbiology: http://www.pharmamicroresources.com

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Main ChangesNew guidance for cleanroom operations:ISO class 8=20 air changes per hoursISO class 7=50 air changes per hourISO class 5=100 air changes per hourIsolators=can have a different justification for air changes and air velocityAn EM programme should only be constructed and executed once airflow mapping and HVAC dynamics have been optimised. Pharmaceutical Microbiology: http://www.pharmamicroresources.com

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Environmental monitoringUSP places emphasis upon particle and viable monitoringParticle counting most important for isolatorsViable monitoring is regarded as semi-quantitativeTrending is the most important aspect of the monitoring programmeIsolated counts a normal phenomenon in conventional cleanrooms which do not require specific corrective action and there is the possibility of a false positivePharmaceutical Microbiology: http://www.pharmamicroresources.com

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Environmental monitoringUSP requires monitoring of:SurfacesAir (room and enclosure)Compressed gasChanges in trend must be investigated, and include assessment of:MaintenanceDisinfectionUnusual events and activitiesPhysical changes e.g. temperature and humidityStaff training


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Environmental monitoringSCDM (TSA) is a suitable medium, incubation at low and high temperatures (20-35oC for not less than 72 hours)Consideration given to fungal medium e.g. SDACertain conditions may require micro-aerophilic monitoring e.g., certain gasses or sterility test failure using anaerobic mediaPharmaceutical Microbiology: http://www.pharmamicroresources.com

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MethodsSettle plates:EU GMP:Semi-quantitative measurement (CFU / 4hours)Require desiccation study.USP 1116:The exposure of open agar-filled Petri dishes, or settling plates, is not to be used for quantitative estimations of the microbial contamination levels of critical environments.Pharmaceutical Microbiology: http://www.pharmamicroresources.com

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Monitoring methodsNo EM programme can prove sterilityEnvironmental control is the most important, supported by EM and media simulationsEM can demonstrate that a clean room is operating with in a consistent state of controlHowever, EM requirements have evolved in a manner that did not fully consider analytical capability and metrologyPharmaceutical Microbiology: http://www.pharmamicroresources.com

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Monitoring methodsAll monitoring methods are flawed:Require people to take themVariability in techniqueRisk of false positivesNo one method can detect all types of contaminationAll methods have relatively poor recoveries (insensitive)Air-samples are particularly weakSurface methods have poor recoveriesSettle plates are not considered quantitativeAll methods are poor at recovering damaged or stressed microorganisms Pharmaceutical Microbiology: http://www.pharmamicroresources.com

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Monitoring methodsTherefore, numerical targets (as CFU) should:Not be used as limits (they are levels)Not be considered specificationsBe seen as informational onlyLow or zero counts are not, by themselves, guarantees for microbial control;Equally, excursions beyond numerical limits are not necessarily and indication of loss of control.Instead:Count non-zero events.Use a contamination recovery rate metric based on historical findingsInference that these should be stable over time with little variation.


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Plate counting debateDEBATEShould not simply count CFU due to the inaccuracies of current environmental monitoring methodsIt is more important to count the incidence rates and investigate out of trend.The limit of quantitation (the number of cfu that can be reported accurately) is 15. If CFU below 15 cfu , do not worry if trend is OK. If above 15 cfu, investigate.


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What does this mean?At very low recovery levels there is no way to establish Alert or Action Levels statistically-the counts are simply too low to make statistical analysis useful.Instead, emphasis should be on incidents.Hits in ISO 5 aseptic environments should be infrequent.Pharmaceutical Microbiology: http://www.pharmamicroresources.com

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What was the pre-USP 2012 situation?Take active air-samples:Microbiological cleanliness levels In Operation cfu/m3

AreaEU GMPFDA GuideUSPAseptic core

usp and its impact on microbiology

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