Review and monitoring the sterility assurance level

One of the most critical operations in pharmaceutical manufacturing is the processing of sterile products. The production of sterile products, specifically the ones that cannot be terminally sterilized,involve complex and demanding processes to prevent the products’ contamination and require a great amount of resources.

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.

The inherent risk of microbiological contamination associated with aseptic operations is critical because it has a direct relation with human health. The difficulty in detecting contamination makes the outcome of these processes less predictable, naturally having higher risk, and being more difficult to control and manage.

 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

Risk mapping of whole aseptic process is a better way to evaluate the probable risk within each steps.

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, 

Factor 1: Facility - Facility controls should to be evaluated for each activity 

Factor 2: Equipment - Equipment involved in aseptic processing should to be evaluates step wise 

Factor 3: Process - Process contrs should to be verified 

Factor 4: Materials - Material management need to be considered  

Factor 5: Utility - All clean utility (Purified water, WFI, PSG & gases) to be consider 

Factor 6: Personnel - Personnel safety, qualification & training need to be evaluate. 

B. Critical process flow of lyophilized injectable formulation :

Figure 2: Lyophilization Process flow from filling end

Risk based approach for sterile injectable manufacturing 

Risk assessment is an attempt to answer the following questions:
–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.

When conducting risk assessment of sterile drug manufacturing process, it is important to cover systems and areas within systems which pose the greatest risk of product contamination and/or require strict control of processing parameters.

An adequate use of quality risk management tools provides better and more informed decisions, enabling, for example, regulators to assert a company’s capability to deal with risk problems and positively affect the thoroughness of direct regulatory supervision. The main purpose of the use of risk management is to support decisions using rational methodology although it is important to underline that compliance with regulatory aspects continues to be a requirement.

Figure 3:Risk ranking for sterile injectable manufacturing process steps

Figure 4: Risk plotting 

1. Facility :

Evaluate the design and layout of the facility (e.g., personnel/material flow, clean room design). Specifications for clean room areas (layout, air filtration, appropriate air classification, pressure differentials between rooms and areas, temperature, and humidity) should be appropriate, and based on the risk of product contamination with particulate matter and microorganisms. 

Review the certification and qualification of the clean room areas to verify the areas meet design criteria and specifications. Certification and qualification typically includes data in support of the following: air flow pattern studies, HEPA (High Efficiency Particulate Air) filter integrity testing, air velocity measurement, non-viable particle, and verification of appropriate pressure differentials, temperature and humidity set points. 

Evaluate the airflow pattern (smoke studies) conducted under dynamic conditions to verify the unidirectional airflow and air turbulence within the critical area where sterilized drug product, containers, and closures are exposed to environmental conditions.

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

As mentioned in Figure 3 (HEPA filter performance verification and routine controls). 

Extend and frequency of cleaning shall be define based on the critical area (Grade A&B).  

Criticality Factors of Monitoring Frequencies:

Criticality Factor	Probability	Frequency of Monitoring
6	Highly Likely	Daily or Each Batch (Pre & Post)
5	Likely	Weekly
4	Moderately Likely	Fortnightly or Bi-weekly
3	Unlikely	Monthly
2	Very Unlikely	Three-monthly or Quarterly
1	High Unlikely	Six-monthly or Semi-annually

 

Example:

Environmental Criticality Factor	Likelihood of Environmental Impact on Finished Product	Definition	Monitoring Frequency
6	Highly Likely	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.	Daily or Each Batch (Pre & Post)
1	High Unlikely	An area that is uncontrolled or where microbial contamination is very unlikely, such as a freezer.	Every 6 Months or Semi-annually

 

2. Utility:

In injectable facility Purified water generation and distribution system , water for injection generation and distribution system and pure steam generation system are the critical utilities. Along with that gases directly used during aseptic processing like compressed air and nitrogen are also consider as critical utility. 

A compressed gas should be of appropriate purity (e.g., free from oil) and its microbiological and particle quality after filtration should be equal to or better than that of the air in the environment into which the gas is introduced. Compressed gases such as air, nitrogen, and carbon dioxide are often used in clean rooms and are frequently employed in purging or overlaying. Membrane filters can be used to filter a compressed gas to meet an appropriate high-quality standard. These filters are often used to produce a sterile compressed gas to conduct operations involving sterile materials, such as components and equipment. For example, we recommend that sterile membrane filters be used for autoclave air lines, lyophilizer vacuum breaks, and tanks containing sterilized materials. Sterilized holding tanks and any contained liquids should be held under positive pressure or appropriately sealed to prevent microbial contamination. Safeguards should be in place to prevent a pressure change that can result in contamination due to back flow of non sterile air or liquid. 

3. Equipment: 

4. Material :

5. Process :

6. Personnel :

Ishikawa diagrams for microbial contamination in aseptic injectables 

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