Blog
Click now to learn from Sue Schniepp, Distinguished Fellow at Regulatory Compliance Associates, as she describes microbial process design and how your team can improve contamination control.
Human microbes live in every part of a human being, including the skin, gut, and nose. Trillions of microorganisms live inside the human body — often outnumbering human cells by 10 to 1. However, microorganisms only make up roughly 1 to 3 percent of the body’s mass because of their tiny size. Sometimes microbes in food can lead to illness, but it is more common for microbes in human body functions to safely live in their host. Additionally, many types of microbes provide unique qualities that help increase life expectancy and human survival in general.
Annex 1
When it comes to microbial control and process design, there are unique drivers listed in the EU’s Annex 1 regulatory guidance that can help your organization. This regulatory compliance guidance contains different types of contamination control requirements.
Further, these drivers come in many different shapes and sizes, but all can impact manufacturing production if not carefully considered.
Sterile Preparations
Manufacturing sterile products covers a wide spectrum of decisions to be considered by the Quality team and manufacturing operations, including:
Sterile product types
- Active substance
- Sterile excipient
- Packaging material
- Finished dosage form
Packaging sizes
- Single unit
- Multiple units
Sterile processes
- Automated systems
- Manual processes
Technologies
- Biotechnology
- Small molecule manufacturing
- Closed systems
Additionally, one of the quality assurance goals of sterile product manufacturing is to minimize risk associated with microbial, particulate, and pyrogen contamination.
Process Design
Contamination sources are the focus of process design and are commonly due to microbial and cellular debris, as well as particulate matter. Understanding how your facility, equipment and employees contribute to uncleanness (whether intentional or not) is essential to contamination control. Lastly, process design should consider each contamination source individually and as a whole to achieve regulatory compliance.
Manufacturing Plant
The facility your product is manufactured in is the first gap analysis that should be conducted. For example, a food manufacturing plant will have a different set of needs to be considered than a pharmaceutical manufacturing environment. Each will have unique requirements based on equipment, environment and process. Further, pharmaceutical production follows unique FDA guidance recommendations that are unlike many commercialized products on the market.
Cleanroom
One of the first priorities your team should understand is clean room classifications and differences in a regulated clean room environment. There are many types of cleanroom services that can help with clean room design and preparing for regulatory compliance (e.g. ISO 7 or ISO 8).
For example, cleanliness standards and cleanroom supplies should be maintained and monitored for environmental conditions. Finally, airlocks for both personnel and equipment should include HEPA (High Efficiency Particulate Air) air filtration to increase air cleanliness and controls that reduce contaminants.
RABS
Restricted Area Barrier Systems (RABS) and isolators can help assure environmental conditions help minimize microbial contamination. Further, a reliable containment strategy should consider the types of human intervention that can impact the critical zone. This often goes hand-in-hand with the type of grade the zone is.
There are four primary types of critical zones:
- Grade A: this area includes high risk operations that must consider air filtration, the aseptic processing line, and filling zone. Additionally, the stopper bowl, open ampoules and vials also must be studied based on contaminates & unidirectional air flow. Finally, process design & SOPs should minimize the number of operators who don’t use barrier protection or glove port
- Grade B: this area is commonly a background cleanroom for Grade A aseptic preparation and filling zone. Most importantly, airflow visualization studies should show that air does not enter from any lower grade cleanrooms to Grade B. Air pressure differentials should be monitored to ensure clean airflow.
- Grade C and D: These types of cleanroom spaces are used for lower risk manufacturing stages in the manufacturing process. The most often use class for Grade C and D are the preparation and filling of terminally sterilized
Finally, it is critically important when analyzing the grade of a zone when it comes to modular clean room or portable clean room designs. Make sure your cleanroom construction team understands the types of certified cleanroom principles that follow regulatory compliance.
Water Systems
A water treatment plant is one of the most critical elements of microbial process design. The water filter system should minimize both particulates and pyrogens to help reduce the potential for contamination. Further, special attention should be given to the different types of water filter products used & how they are monitored and maintained over time. Nevertheless, water flow should remain forceful & consistent through water filtration pipes to minimize microbial adhesion & the risks associated with biofilm formation.
Sterilizing Agent
When using a pure steam generator as a sterilizing agent, the design should be correctly purified. Additionally, these agents of sterilization should be designed & validated to confirm steam quality meets both chemical levels and endotoxin levels. For the same reason, measure your steam quality for any additional additives that can cause either contamination of your product or manufacturing equipment.
Central Vacuum System
Understanding when gases come into contact with the product or container surfaces is critical during process design. For example, here are process design concepts to validate proper chemical, particulate, and microbial quality:
- Relevant parameters (e.g. oil and water content) should be specified in the documentation
- Consider the use cases inside the facility & type of gas being used during the process
- Respect the gas generation system & if the design complies with the Pharmacopoeia monograph
Gases used in aseptic processes should always be filtered through a sterilizing filter. If your sterilizing filter is used on a batch basis, consider integrity testing the results during batch certification. Finally, any backflow from vacuum systems or pressure systems can produce hazards to the product. Have your quality team consistently review the mechanisms that prevent backflow when the systems are shut down.
Hydraulic Systems
Manufacturing equipment connected by hydraulics or heating & cooling systems, when possible, should be preferably outside the filling room. Equally important, pump hydraulics or fluid hydraulics located in the filling room should include design controls to contain any spillage. Leaks from these types of systems could pose a contamination risk to the product that should be detectable.
Finally, incorporating an indication system can help monitor leakage scenarios where contamination can become an urgent problem. This can include manufacturing technology such as tank gauges, a tank level sensor, and advanced water level monitor functionality.
