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Regulations………of course!
• Applicable regulations for Sterile Manufacturingin the EU market and
Monitoring of Operating Theatres in Hospitals:
• UNI-EN-ISO 14644/1-2-3 for cleanroom classification and testing.
• UNI-EN-ISO 14698/1-2 for biocontamination control in cleanroom.
• Pharmacopoeias: USP, JP, EP
• HTM 03-01 referring to Microbiological Commissioning and Monitoring of
Operating Theatre Suites
• Annex 1 of the EU Guide to Good Manufacturing Practice (Orange Guide)
(2003)
• Annex 1 Consultation Document Draft (2017)
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Typical Human Upper Respiratory Flora
BACTERIUM Nose Pharynx Mouth
Staphylococcus epidermidis ++ ++ ++
Staphylococcus aureus* + + +
Streptococcus mitis + ++
Streptococcussalivarius ++ ++
Streptococcus mutans* + ++
Streptococcus pneumoniae* +/- + +
Streptococcus pyogenes + +
Neisseria sp. + ++ +
Neisseria meningitidis + ++ +
Proteus sp. + + +
Haemophilus influenzae* + + +
Lactobacillus sp. + ++
Corynebacteria ++ + +
Actinomycetes + +
Spirochetes + ++
Mycoplasmas + +
Green: Will grow
on TSA/TSB
Red: Will NOT
grow* on TSA/TSB
Orange: May
Grow on TSA/TSB
*Under typical
incubation conditions.
“Regulatory Expectations for Aseptically
Produced Parenterals”
Ian Symonds, Director AsepticQuality
Assurance , GlaxoSmithKline
December 2009PDA Meeting, Milan
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Current Sampling
•Filter Area = 6m2
•Air Rate = 0.45m/S
•Volume Of Air In 1min =162m3
•Volume Of Air, 1hour = 9,720m3
•Volume Of Air, 8hr Shift = 77,760m3
• Active Air Sample = 4m3 0.005 % Air
• Continuous Particle Monitoring = 16m3 0.02 % Air
• Surface Monitoring;
–10 Contact Plates = 0.0250m2 = 0.417 % Surface*
–10 Swabs = 0.0250m2 = 0.417 % Surface
• Based upon the footprint of the filling machine area within the RABS. Note: the actual total surface area would be
much higher
15. 15
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Annex 1 of the GMP Guide to the Manufacture of Sterile Medicinal Products (the “Orange Guide”) is changing
the way environmental monitoring of viable organisms performed from routine sampling to continuous
monitoring.
9.27 Continuous monitoringin grade A and B areas should be undertaken for the full duration of critical processing,
including equipment(aseptic setup) assemblyand filling operations (i.e., an understanding of function and interactions of
each clean area). The monitoring should beperformed in such a way that all interventions, transientevents and any
system deterioration would becaptured and any riskcaused by interventions of themonitoringoperations is avoided.
9.28 Rapid microbial monitoring methods maybe adopted after validation as long as they are demonstrated to be at least
equivalent to theestablished methodology.
9.33 If microorganisms aredetected in a gradeA or B zone, they should beidentified to species level and theimpact of
such microorganismson product quality(for each batch implicated) and state of controlshould be evaluated.
Consideration mayalso begiven to theidentification of gradeC and Dcontaminantsand therequirements should be
defined in thecontaminationcontrol strategy.
In addition, ISO 14698 specifies some more air sampler specific criteria for active air sampling:
• Must entrap particles down to 1µm
• Sample at least 1m³
• Operate within 1 foot of critical area
• Settle plates can be used for up to 4 hours
As monitoring was not required throughout the process,
sampling was usually performed before the start and after
the end of a process. This was seen as ‘down time’ in the
process which lead to an array of rapid cubic metre air
samplers becoming available. These are samplers not
monitors!
The Need for Monitoring not
Sampling
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ImpactAir®and ISO-140®
Environmental Monitoring Solutions
• ImpactAir & ISO-140– Air Monitors
• Fully validated for ISO 14698-1 for Physical & Biological Efficiency
• Class leading d50 = 0.42µ
• Unique RELIABLE dynamic height adjustment*
• Consistent d50 throughout run*
• Proven monitoring technology
• Up to 4hrs or 6.8m³ per plate
• Does not shed particles
• HEPA filtered exhaust
• Robust stainless Steel construction
• Ultra low vibration
• Low power (<60 wats)
• Optional remote control unit (RCU)
• Time correlated results
• Drop in replacement for Air Trace
*IP protected
ISO-140 & ISO-CON
Controller
22. 22
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ISO-90® –
Critical Location Monitoring
• Designed to Monitor Critical Locations
• 4 hours on 9cm agar plate
• Fully validated for ISO 14698-1 for Physical & Biological Efficiency
• d50 <0.75µ
• 125mm diameter
• Proven monitoring technology
• Does not shed particles
• HEPA filtered exhaust – environment
• 9cm Agar plate
• Robust stainless Steel construction
• Ultra low vibration
• Low power
• Time correlated results
In current development is a ground-breaking ultra small monitor designed to monitor
critical locations. It draws air in at a slower rate to minimise air flow disturbance yet
meeting all of the requirements of Annex 1 whilst using a 9cm agar plate.