Root cause identification for NVPC Excursion

This articles cover all the critical aspects for identifying probable root causes for non viable particle count excursion/failure at Grade A conditions.

1. Man:

• Training 
• Hygiene 
• Qualification 
• Intervention 
• Aseptic practice
• Sampling 
• Stress/ Work load
• Cross contamination 
• Sampling/EM activity
• Improper Tyvek bag tear off

2. Machine:

a. AHU

• Improper fixing HEPA to ceiling
• HEPA filter damage/leakage/Age 
• Door Interlock

b. Vial Washing 

• Improper cleaning of vials due to,
• Low pressure in utility
• Filter quality used for utility
• improper handling of vials
• Dismantled machine guard

c. Depyrogenation tunnel

• Final washer to tunnel in feed GAP
• HEPA filter damage/leakage/Age 
• Dirt chaired in 350 temperature 
•  Mope lint in tunnel track 
• DP disturbed
• Entry and exit flap setting

d. Online particle counter 

• Amplitude of the sensor output function
• Effect of flow on sizing in counter/Pulse Height
• Isokinetic sample heads shall be used in unidirectional airflow systems
• VHP tolerant flow path and optics
• Illumination Uniformity Affects Resolution

e. Filling Isolator

• Improper fixing HEPA/integrity
• LAF trip/Interruption in power supply
• Isolator Leakage
• Leakage from Glove/sleeve system
• Turbulence
• Pressure balance tunnel cool zone to filling 
• Turbulence as return riser obstruct with material
• Sharp ages of machine
• Concealed base of Isolator
• Isokinatic probe near Isolator exhaust create turbulence in air flow 

f. Filling and bunging machine

• Machine speed variation
• Vibration
• Run machine Auto to manual mode
• Post PM, improper assembling 
• Sharp ages of machine

g. Other

• Use of sharp item within filling activity
• Vacuum Cleaner efficiency
• vacuum cleaner filter bag damage

3. Material:

• Mope quality
• Garment quality
• Gloves quality
• CG screen aging
• Tyvek bag 
• Media plate wrapper
• Non GMP tooling used
• Damage bag of Vacuum Cleaner
• CA/Nitrogen purging
• Integrity Air Filters use for CA/Nitrogen 
• Drug product crystal formation from spillage
• Media spillage

4. Method:

• Placement of Isokinetic probe
• Sampling point selection
• Flushing with "0" Filter for initial run
• Cleaning of Isokinetic probe
• Tube length and distance
• Lid of Probe opening during manual cleaning 
• Setting of warning level
• Alert/Action level and Trending 
• Cleaning of area and equipment
• Use/ generation aerosol/powder in the filling area 
• Man and material movement
• Machine stoppage reporting procedure
• Post brake/stoppage start up procedure 
• Qualification of area and equipment 
• Break Down maintenance
• HEPA replacement frequency

5. Measurement:

• Online particle counter 
• Calibration of probe
• Air velocity or flow rate of the particle counter
• Tubing length
• Number of tubing bends
• The radius of these bends
• Tubing diameter
• Tubing material
• Ageing of sampling tube
• Distance of installed probe
• Replacement frequency
• Bend in sampling tube
• PM of NVPC sampler 

6. Environment:

• ACPH 
• Air Velocity
• Pressure balance/drop
• Power fluctuation/fail
• Inadequate cleaning
• Laminar air flow
• Unidirectional Air flow

7. Controls:

• Failure of alarm
• Improper set limit
• Velocity detection sensor
• Pressure low alarm
• Door position sensor of BMS
• Disable machine controls & sensor

8. Intervention:

• Intervention proximity from probe
• Complexity of intervention
• Duration of intervention
• New interventions performed (if any)
• Unidentified interventions
• Corrective & Inherent intervention