Aseptic manufacturing Flashcards
Aseptic manufacture, what are the main process safeguards.
Facility design (MALs and PALs, interlock controls) and grading, access control, HVAC - HEPA filtered air, DP, and air change rates. Unidirectional flow at critical points, closed systems where possible, filling and open manipulations in grade A zone, personnel training, gowning, environmental monitoring, media fill etc
What is the suitable environmental condition for aseptic fill? Does the room and the filling point have to be class 100?
Aseptic fill so not terminally sterilised then all open manipulations including final fill should be controlled under Grade A conditions, this might be a Grade A area / RABs / LAF etc within a grade B room
In an aseptic manufacturing area for an IV product what kind of conditions would you expect?
Grade A Sterile (RABS),
Background Area Grade B / C
Gowning -Sterile
Environmental Monitoring
Autoclave / Radiation / Oven
How would you qualify this environment?
Contamination Control Strategy
Settle Plates, Contact Plates, Air Samplers, Particle Monitoring Points - Close proximity to exposed product, Frequent touch points, Intervention Locations,
Smoke Visualisation Studies
Air Change Rates
Room Pressure Differentials
What are the specifications for Grade A?
< 1cfu – Settle Plates, contact Plates,
Maximum permitted number of particles per m3 equal to or greater than the tabulated size 0.5µm 3 520 5µm 20
What are the patient risks associated with IV sterile injection products?
Avoids first pass metabolism
Directly into patients blood stream – avoids all bodies natural defences
Potentially immunocompromised patients
What extra measures would you expect if the products were cytotoxic?
Dedicated Facilities and Utilities
High risk of allergic reaction- adverse side effects in patients, patient can’t be pregnant
Contain chemicals which are toxic to cells – issues with exposure for manufactures and administrators.
What needs to be in place for sterile manufacture?
Contamination control strategy including training, gowning, monitoring, facility design and controls, aseptic technique etc
What is the difference between aseptic processing and terminal sterilisation?
Terminal sterilisation is done at the end of the manufacturing process to heat treat the final product within its primary container - manufacturing usually within a Grade C area.
Aseptic processing is risky and is used when the final product cannot be terminally sterilised as it will denature / spoil the final product - contamination control and operator aseptic technique is key - Final fill and open manipulations in Grade A.
How would you validate aseptic manufacture?
Usual change control, impact assessment, IQ, OQ, PQ, PV but then would follow with media fills - number to be completed should be risk assessed but usually 3 consecutive
How would you set up an aseptic manufacturing facility?
What would expect to be in place for operator training?
How would you validate the gowning procedure for Operators?
How would you design the environmental monitoring programme?
What is the time for settle plates, if your operation goes beyond the 4hr’s would you expect further settle plates?
Raise Change Control
Quality Risk Assessment – with a multi-functional team
Contamination Control Strategy
What would expect to be in place for operator training?
General GMP / Steriles Focused GMP
Gowning Validation
Operator Media Trials
PST Validation
Task Specific Training
How would you validate the gowning procedure for Operators?
Get the operator to perform gowning and then take personnel monitoring.
Typically we would take plates from hood, goggles, chest, forearm, Finger Dab and side of boot.
How would you design the environmental monitoring programme? – Do you mean a routine environmental monitoring program?
Follow the guidance outlined in Annex 1
Based on formal risk assessment during cleanroom qualification taking in to consideration the contamination control strategy.
What is the time for settle plates, if your operation goes beyond the 4hr’s would you expect further settle plates?
4 hours - +/- 15 mins – Max 6 hours (still incubate if no visible drying of agar)
Yes new settle plates every 4 hours – critical processes must be continuously monitored as per Annex 1
How would you design an environmental monitoring plan
Guidance would be outlined in EudraLex Volume 4 - Annex 1 , Cleanroom Classification - ISO14644
Raise Change Control
Perform Impact Assessment - Include Quality, Production, Microbiologist,
Concerns:-
As a minimum, the programme should address the following elements:
Types of monitoring methods
Culture media and incubation conditions
Frequency of environmental monitoring
Selection of sample sites (where monitoring will take place)
Maps showing sample locations
Duration of monitoring
When and where the samples are taken (i.e. during or at the conclusion of operations)
Method statements describing how samples are taken and methods describing how samples are handled
Clear responsibilities describing who can take the samples
Processing and incubation of samples
Alert and action levels
Data analysis, including trending
Investigative responses to action levels excursions,
Appropriate corrective and preventative actions for action level excursions
Consideration if special types of environmental monitoring are required (such as the use of selective agars for objectionable microorganisms or anaerobic monitoring)
Review current Contamination Control Strategy for the Facility if there is one as this will form the basis for your EM Risk Assessment
Elements that should be considered as part of a Contamination Control Strategy will include:
Design of the plant and processes. Premises and equipment. Personnel. Utilities. Raw material controls. Product containers and closures. Vendor approval –key suppliers. Outsourced services, such as sterilization, ensure the process is operating correctly. Process risk assessment. Process validation. Preventative maintenance. Cleaning and disinfection. Monitoring systems - the introduction of scientifically sound, modern methods that optimize the detection of environmental contamination. Prevention – trending, investigation, corrective, and preventive actions (CAPA). Active air-sampling: volumetric air-sampler Passive air-sampling: settle plates Surface samples: contact (RODAC) plates and swabs Personnel samples: finger plates and gown plates Non - Viable Particulate Monitoring considerations As Built ( completed room no equipment or personnel), At Rest (all equipment installed no personnel), Operational (all equipment and personnel working to an agreed procedure) Continuous monitoring within the Grade A Location of the sample point(s) - close to activity but not interfering with routine processes based on 'worst case' Frequency of Monitoring Viable Monitoring Continuous monitoring during operation for Steriles Number of samples and location will be based on room size, layout and activities being performed (Frequent touch points, areas that pose high product risk). Types of plate non-selective (TSA) - Bacteria / selective Fungai, Fungai (SDA) Incubation - For bacteria: 30-35°C , For fungi: 20-25°C Ensure Action / Alert Levels established as well as Trending Process to investigate organisms that are considered 'Objectionable'
Types of Monitoring (Viable /Non-Viable)
Active air-sampling: volumetric air-sampler
Passive air-sampling: settle plates
Surface samples: contact (RODAC) plates and swabs
Personnel samples: finger plates and gown plates
Non - Viable Particulate Monitoring considerations As Built ( completed room no equipment or personnel), At Rest (all equipment installed no personnel), Operational (all equipment and personnel working to an agreed procedure) Continuous monitoring within the Grade A Location of the sample point(s) - close to activity but not interfering with routine processes based on 'worst case' Frequency of Monitoring Viable Monitoring Continuous monitoring during operation for Steriles Number of samples and location will be based on room size, layout and activities being performed (Frequent touch points, areas that pose high product risk). Types of plate non-selective (TSA) - Bacteria / selective Fungai, Fungai (SDA) Incubation - For bacteria: 30-35°C , For fungi: 20-25°C Ensure Action / Alert Levels established as well as Trending Process to investigate organisms that are considered 'Objectionable'
Describe how you would set up an environmental monitoring programme for a sterile site
Tell me more about how you would use a risk-based approach
Raise Change Control
Annex 1 – Contamination Control Strategy
HVAC / Air Supply / Extract /
People – gowning, training, contact points,
Settle Plates, Active Air Samples, Particle Monitoring Points, Contact Plates, Personnel Monitoring,
Talk about Grade A – D
Grade C and D should be monitored quarterly, based on data and risk assessment
