This article is covering section 9 which describes the annex 1 guidance for Environmental and Process Monitoring. Section 9 is now a centralized location for monitoring activities which includes microbiological, particulate and media fills.
If we start with environmental monitoring, section 9 calls for a documented EM Program aimed at providing assurance of appropriate level of cleanliness. It should be able to detect limit excursions and triggers root cause investigations. Monitoring should use risk-based approaches for locations, frequency, incubation conditions etc. Trending requirements have been expanded to include numbers, frequency of excursion, common causes, and changes in flora. Rapid methods for monitoring are now included and the limits applied to microbiological and particulate monitoring are as set out in section 4. This is with the exception that here glove print (finger dabs) and 5.0mm particle limits (for Grade A and grade B at rest) are included.
For non-viable monitoring data should be frequently checked against limits and where exceeded, alarms should be triggered. There should be continuous monitoring of particles in Grade A areas. Monitoring should be for the full duration including set up.
Viables monitoring requirements are enhanced. Monitoring should also include “at rest” such as after disinfection to check for potential risks. There should be continuous viable air monitoring in Grade A by active air sampler or settle plates. Gowns should be monitored on each exit and gloves and gowns replaced after monitoring. Sampling methods should be fully understood including recovery efficiency data. The Quality Unit should have oversight of Production performed monitoring. Grade A/B isolates identified to species level and the impact evaluated. A similar approach should be considered for C and D areas where loss of control is suspected or where there is detection of mold and bacterial spore formers which are more difficult to control.
The rest of the section is about the Aseptic Process simulation (APS) which is considered as one way of validating the effectiveness of an aseptic process. It should not be used to justify practices posing unnecessary risks of contamination.
The sterile medium (including a surrogate material) used to simulate a product should imitate physical product characteristics. Process stages should not impact of growth of potential microorganisms for example heating and cooling or freezing stages etc. Media should be shown to support microbial growth including local isolates.
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.
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Annex 1 is now aligned to the FDA 2004 aseptic processing guide. Planning an APS should therefore include for example, maximum hold times for product and equipment exposed during the aseptic process, container closure combinations with matrixing being permitted, fill duration, units filled and line speed. Beginning and end of campaigns should be considered along with container fill volume (ensuring all internal surfaces are wetted while leaving a head space that can support microbial growth). Media should be filled into clear containers or a validated detection method for inspection. Routinely occurring interventions should be simulated.
All operators permitted to work in aseptic manufacture should attend once per year while all others entering grade A/B should participate at a risk-based frequency. For manual filling, operators should attend every 6 months.
Runs should be fully documented and units filled reconciled. Nominal batch size for APS is 5,000-10,000 units. Aborting a media fill should only occur under the same conditions that would lead to as a product batch being terminated.
Annex 1 now give guidance on handling more complex application of an APS. Semi solids for example may need an alternative process where heating and cooling stages are involved or viscolisers are added as surrogate materials. Inert atmospheres normally need to be substituted with air. With freeze drying, the whole process chain must be included i.e., filling, transport, loading, dwell time, offloading etc. Freezing can kill microorganisms and vacuums can stress them so full vacuum steps should be avoided.
Prior to incubation the units should be tumbled, mixed, agitated etc to ensure all surfaces of the container are wetted. Units should be incubated without delay. As there are no consistent conditions recommended, Annex 1 requires that incubation conditions to be scientifically justified.
Each unit is then inspected for evidence of microbial growth by appropriately train staff for detecting microbial contamination and under conditions that facilitate detection. This labour-intensive process can be substituted by a validated automated method such head space analysis. Finally, if any microorganisms are detected they should be identified to species level where possible.
Acceptance criteria have been tightened such that if one or more contaminated units are found the media fill fails. Investigate for root cause is the next step so that corrective actions can implemented before recommencing production following revalidation, typically require three consecutive successful media fills. There should also be a review records since last successful APS to assess risk of potential sterile breaches and this should include all batches not yet released.
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.
