The objectives of review includes:
- Obtain information on operations impacting on sterility, to identify areas for improvement and correction.
- Evaluate current good manufacturing practices in the sterile drug industry.
- Initiate appropriate action against manufacturers observed to be out of compliance.
Aseptic processing presents a higher risk of microbial contamination of the product than terminal sterilization. In an aseptic filling process, the drug product, containers and closures are sterilized separately and then brought together under an extremely high quality environmental condition designed to reduce the possibility of a non-sterile unit. Aseptic processing involves more variables than terminal sterilization. Any manual or mechanical manipulation of the sterilized drug, containers, or closures prior to or during aseptic filling and assembly poses the risk of microbial contamination.
Some types of aseptic processing involve manual manipulations of sterile components, containers, and closures in addition to routine operator interventions in the critical area. Humans are a significant source of contamination in traditional aseptic processing, especially in production lines that require operators to routinely enter critical areas (Class 100, ISO 5, or Grade A) of the filling line. Aseptic processing systems based on more advanced control-based technologies, such as Restricted Access Barrier Systems (RABS) and Blow-Fill-Seal systems, are designed to reduce human interventions in the critical areas of the fill line while an isolator system completely separates the aseptic filling line from the external environment and minimizes employee interaction with the critical area.
A. Critical process flow of liquid injectable formulation :
Figure 1: Liquid injectable formulation flow
|
As per Figure 1 all the critical process steps are mentioned with control, but not limited too. Concept of sterility assurance comes with step wise evaluation of aseptic process. Risk based evaluation should to be performed on 6 factors, as mentioned below,
B. Critical process flow of lyophilized injectable formulation :
Figure 2: Lyophilization Process flow from filling end |
Risk based approach for sterile injectable manufacturing
–What can go wrong?
•Risk
–How bad are the consequences?
•Severity
–How often does/will it happen?
•Probability of Occurrence
–If it happened, how would we know?
•Likelihood of Detection
–Is the risk acceptable?
•Risk Evaluation, Remediation
Although for many years, the concept of risk management also has been applied in the pharmaceutical industry in an informal manner, formal applications are more recent and still considered limited.
Figure 3:Risk ranking for sterile injectable manufacturing process steps |
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Figure 4: Risk plotting |
1. Facility :
Figure 3 : HEPA filter performance verification and routine controls |
Figure 4: Fishbone Diagram (Ishikawa) for assessment microbial risk in clean rooms |
Clean room are very critical in pharmaceutical manufacturing. Facility should to be design such a way, it should allow minimum contaminants from outside. Concept of clean room is like onion. Inner side is cleaner than outer. Heating Ventilating Air Conditioning system will control and monitor the temperature, humidity and pressure differential through Building management system. Periodic qualification HEPA shall be performed Air velocity Test and Air changes Calculation
- HEPA Filter Leakage Test
- Differential Pressure Monitoring
- Temperature and Humidity Monitoring/Mapping
- Non-Viable Particle Count Monitoring
- Microbial Monitoring
- Air Flow Pattern Study
- Recovery
Criticality Factor
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Probability
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Frequency of Monitoring
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6
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Highly Likely
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Daily or Each Batch (Pre & Post)
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5
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Likely
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Weekly
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4
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Moderately Likely
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Fortnightly or Bi-weekly
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3
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Unlikely
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Monthly
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2
|
Very Unlikely
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Three-monthly or Quarterly
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1
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High Unlikely
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Six-monthly or Semi-annually
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Environmental Criticality Factor
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Likelihood of Environmental Impact on Finished Product
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Definition
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Monitoring Frequency
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6
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Highly Likely
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Aseptic filling where no further processing takes place. Here the risk of contamination would have a considerable product impact because contaminants could not be reduced or removed by further processing.<
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Daily or Each Batch (Pre & Post)
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1
|
High Unlikely
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An area that is uncontrolled or
where microbial contamination is very unlikely, such as a freezer.
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Every 6 Months
or Semi-annually
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An informative piece of writing!Glad that i came across with your blog post and got to know about isolator technology. Although,Isolators have been around the Pharmaceutical Industry since the early 1980s,but still i didn't know about it.
An informative piece of writing!Glad that i came across with your blog post and got to know about isolator technology. Although,Isolators have been around the Pharmaceutical Industry since the early 1980s,but still i didn't know about it.